KR20190090065A - Novel Imidazopyridazine Compounds and their Use - Google Patents

Abstract

The invention reactive to a novel imidazo pyridazine compound and its pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for preparing them, and their actual PI ₃ K inhibitory effects as PI ₃ K inhibition of formula (I) Inflammatory diseases, autoimmune diseases or cancers, for example, in the treatment of cancer.

Description

Novel imidazopyridazine compounds and their use < RTI ID = 0.0 >

The present invention relates to a novel imidazopyridazine compound, its pharmaceutical composition, a process for its preparation and its use.

PI ₃ K (phosphatidylinositol-3-kinase) -mediated signal pathway plays an important role in the development and progression of various malignant tumors.

PI ₃ Ks is a lipid kinase that phosphorylates the 3'-hydroxy group of PtdIns (phosphatidylinositol) and phosphoinositide (a phosphorylated derivative of PtdIns). These enzymes are classified into three categories according to their substrate preference and structure: class (I), class (II) and class (III). Of these three categories, Class (I) has been extensively studied. Class (I) PI ₃ Ks includes two sub-classes: class (IA) and class (IB). There are three genes encoding the class (IA) catalyst homologs. Each of which encodes a protein product of about 110 kDa, designated p110?, P110? And p110?. These protein products of at least five such polymorph (p85α, p55α, p50α, p85 p110 β and p55γ) to which class (IA) The dimer stable two kinds with the control sub-unit, that is, PI ₃ Kα, PI ₃ Kβ and PI ₃ K < / RTI > There is a single class (IB) enzyme p110? associated with a unique regulatory subunit, p101. This dimer is also called PI ₃ Kγ.

A total of four class (I) catalytic PI ₃ K homologs all exhibit characteristic expression patterns in the body . P110 alpha and p110 beta are widely expressed while p110 gamma and p110 delta are mainly found in white blood cells (Sundstrom TJ et al, Org. Biomol. Chem., 2009, 7, 840-850).

The P110 delta catalytic subunit of class (IA) PI ₃ K may play an important role in the growth and activation of murine B cells. P110 delta-deficient mice showed partial block in early B cell growth, a sharp decrease in the number of mature spleen B cells, and almost no B1 subpopulation of mature B cells when transferred from pro-B to pre-B cells. A small number of B cells, which can be isolated from the spleen of p110δ-deficient mice, do not proliferate to anti-IgM after BCR (B cell receptor) colonization. In addition, polyclonal B-cell myotenic lipopolysaccharide and anti-CD40 response to the reaction may also fail. p110 delta-deficient mice also do not produce an effective antibody response to TI-2 (T-independent type II) antigen (Okkenhaug K, Science. 2002, 297: 1031-4).

In cancer cells, PI ₃ K / AKT pathway regulatory disorder and hyperactivity were confirmed. Due to the specific role of p110 delta in B-cell growth, B-cell lymphoproliferative disorders such as CLL (chronic lymphocytic leukemia) and NHL (non-Hodgkin's lymphoma) can be targeted as a drug.

PI ₃ Kδ is implicated internally in mammalian immune system functions such as signaling of T-cells, B-cells, mast cells, dendritic cells, neutrophils, NK cells and mononuclear proximal cells. Numerous experiments with PI ₃ Kδ inhibitors or PI ₃ Kδ deficient animals show that PI ₃ Kδ is an autoimmune disease such as respiratory diseases and rheumatoid arthritis, such as allergic respiratory inflammation [Nashed BF, et al. Eur J Immunol. 2007; 37 (2): 416-24) and acute lung injury [Puri KD, et al. Blood. 2004; 103 (9): 3448-56). Due to its inalienable role in immune system function, PI ₃ Kδ is also involved in the treatment of allergic diseases, inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, rheumatoid arthritis, lupus, asthma, emphysema and other respiratory diseases It is also accompanied by a number of diseases related to the immune response.

Previous studies have shown that the potential and selective PI ₃ Kδ inhibitor Idelaresis (CAL-101) has broad anti-cancer activity against cancer-associated cancer cells (Vanhaesebroeck B, Cancer Cell, 2014 , 25: 269-71). WO2005113556, US20130071212, and US20140179718 also disclose compounds useful in the treatment of autoimmune diseases and cancers, particularly cancer of the blood.

For the treatment of autoimmune diseases and cancer, in particular, a blood cancer related disorders, optionally, provides the PI ₃ K-modulating compound, which comprises adjusting the PI ₃ Kδ.

In particular the compounds of the formula (I)

And a solvate, racemic mixture, enantiomer, diastereoisomer, tautomer and / or pharmaceutically acceptable salt thereof, wherein W, R _1, R ₂ and m are as defined herein.

Also provided are pharmaceutical compositions comprising a compound of formula (I) (e.g., any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

Also provided are methods of inhibiting PI ₃ K activity in vivo or in vitro , comprising contacting an effective amount of a compound of formula (I) (eg, any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof with a PI ₃ K Method.

Also provided is a method of inhibiting PI ₃ K in said subject, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) (e.g., any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof. Lt; RTI ID = 0.0 > and / or < / RTI >

Diseases that respond to PI ₃ K inhibition are selected from inflammatory diseases, autoimmune diseases and cancer.

Also provided are compounds of formula (I) (e. G. Any of the compounds described herein) and / or pharmaceutically acceptable salts thereof, as described herein, for the treatment of diseases responsive to PI ₃ K inhibition.

Also provided is the use of a compound of formula (I) (eg, any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof as described herein for the manufacture of a medicament for treating a disease responsive to PI ₃ K inhibition do.

The subject matter described herein may be a human or an animal. In some embodiments, the subject matter described herein is a human.

In addition, compounds of formula (II) that can be used in the preparation of compounds of formula (I)

And / or a salt, racemic mixture or diastereomer thereof, wherein Ar and R ₂ are as defined in formula (I) and all are defined as follows.

Figure 1 shows the effect of the compound (4) prepared in Example 1 on anti-IgD-derived B cell activation in female Wistar rats in a dose and time dependent manner. Data for activated B cells are expressed as mean ± SEM (n = 3). Plasma concentration data are expressed as means ± SD (n = 3). The data are analyzed as ANOVA followed by Dunnet's test band (vehicle + anti-IgD) group. ## represents p <0.01 (vehicle + PBS) group, ** represents p <0.01 (vehicle + anti-IgD) group.
Figure 2 shows the effect of the compound (4) prepared in Example 1 on the foot size of CIA wistar rats. The hind foot size was measured daily with a volumetric flow meter. Foot size data are presented as mean ± SEM (n = 6 in normal rat group, n = 8 in rest rat group). The remaining groups are vehicle control, different doses of compound (4) group (QD) and positive control (QOD). Analyze the bottom area (AUC) of the average foot swelling with one-way ANOVA using Sigma statistical analysis software, perform Fisher's least significant difference (LSD) test, and calculate the p value. ## indicates p <0.01 versus normal, ** indicates p <0.01 versus vehicle control.

Justice

As used herein, the following terms, phrases, and symbols generally have the following meanings, unless the context clearly dictates otherwise.

The middle line ("-"), which is not between two characters or symbols, indicates the attachment point of the substituent. For example, -O (C ₁ - ₄ alkyl) is attached via an oxygen atom. However, if the point of attachment of the functional group to a person skilled in the art is clear, for example, in a halo substitution, the symbol "-" may be omitted.

Unless expressly indicated otherwise, the terms "a "," an ", and the like refer to one or more.

As used herein, the term "alkyl" refers to a linear or branched saturated hydrocarbon radical containing from 1 to 18 carbon atoms, such as from 1 to 12 carbon atoms, still from 1 to 6 carbon atoms, &Lt; / RTI &gt; and from 1 to 4 carbon atoms. For example, "C _1-6 alkyl" refers to an alkyl that is in the scope of "alkyl" and contains from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n- ("n-Bu"), i-butyl ("i-Bu"), s-butyl ("s- Bu") and t-butyl

As used herein, the term "alkenyl" refers to an alkyl group having from 2 to 10, such as from 2 to 6, carbon atoms selected from those having one or more, for example, 1,2 or 3 C = C double bonds, Represents a linear or branched saturated hydrocarbon radical selected from those having 2 to 4 carbon atoms. For example, "C _2-6 alkenyl" refers to an alkenyl having 2 to 6 carbon atoms, in the alkenyl range. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propyl and 2-butenyl.

The term "alkynyl &quot;, as used herein, refers to an alkynyl group having one or more, such as one, two, or three C = C bonds and 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, Lt; / RTI &gt; to 4 carbon atoms. For example, "C _2-6 alkynyl" denotes one C = C triple bond and alkynyl having 2 to 6 carbon atoms. Examples of the alkynyl group include, but are not limited to, ethynyl, 2-propynyl and 2-butynyl.

As used herein, the term "halo" includes fluoro, chloro, bromo, and iodo, and as used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.

As used herein, the term "haloalkyl" refers to an alkyl radical as defined herein wherein one or more, for example 1, 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, Are all the same or different from each other. In some embodiments, as used herein, the term "haloalkyl" refers to an alkyl radical as defined herein wherein two or more, e.g., two, three, four or five, hydrogen atoms are replaced by halogen atoms , These halogen atoms are all the same. In another embodiment, as used herein, the term "haloalkyl" refers to an alkyl radical as defined herein wherein two or more hydrogen atoms, e.g., two, three, four or five, And these halogen atoms are not all mutually the same. Examples of haloalkyl groups include, but are not limited to, -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , and the like.

As used herein, the term "alkoxy" denotes an -O-alkyl group, wherein alkyl is as defined above. Examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n -propyloxy, i -propyloxy, n -butyloxy, i -butyloxy, t -butyloxy, pentyloxy, Lt; / RTI &gt;

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical having one or more, such as one or two rings, and also having from 3 to 12, such as from 3 to 8, It can have 6 carbon atoms. For example, "C _3-8 cycloalkyl" refers to a cycloalkyl having 3 to 8 carbon atoms in the ring. Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, the term "aryl" refers to a monocyclic ring or a carbocyclic hydrocarbon radical of a fused ring having 6 to 14 ring carbon atoms, such as 6 to 12 ring carbon atoms, wherein the ring is aromatic, Is not a heteroaryl as defined below, and the point of attachment may be on an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, indenyl, indanyl, azulenyl, especially phenyl and naphthalenyl .

-전자수가 4n+2와 같으며, 이때의n은 0 또는 6을 넘지 않는 양의 정수이다.As used herein, "aryl" or "aromatic" is according to the Huckel's method,

- the number of electrons is equal to 4 n +2, where n is a positive integer not exceeding 0 or 6.

The term "heterocyclyl" or "heterocyclic ", as used herein, refers to a heterocyclic group containing at least one carbon atom and at least one heteroatom selected from O, S and N, such as from one to four heteroatoms, Membered monocyclic, bicyclic, and tricyclic saturated and partially unsaturated rings consisting of one or two heteroatoms, more preferably one or two heteroatoms. The attachment point of the heterocyclyl can be on a hetero atom or on carbon. "Heterocyclyl" or "heterocyclic" also refers to a monocyclic ring or fused ring comprising at least one heteroatom selected from O, S and N and, in the case of a fused ring, N, and is not heteroaryl or aryl of other rings, and the point of attachment may be on a heterocyclic ring or other ring.

As used herein, the term "heteroaryl"

Two, or three, for example, one, two, or three ring atoms having 5, 6, or 7 ring atoms, preferably 6 ring atoms, and independently selected from N, O, and S A monocyclic aromatic hydrocarbon radical containing one or two heteroatoms and the remaining ring atoms carbon; And

For example, 1, 2, 3 or 4 ring atoms having 8 to 12 ring atoms, for example, 9 or 10 ring atoms, and independently selected from N, O and S (especially N) , Such as a bicyclic aromatic hydrocarbon radical containing one or two heteroatoms and the remaining ring atoms being carbon, wherein the ring is aromatic. For example, bicyclic heteroaryls include 5- to 6-membered heteroaryl rings or 5- to 6-membered heterocyclic aromatic rings joined to aryl rings wherein the attachment point is a heteroaromatic ring or a heteroaryl ring / May be present on an aryl ring.

When the total number of S and O atoms of the heteroaryl group exceeds 1, these hetero atoms are not adjacent to each other.

Heteroaryl groups also include those in which the N heteroatom is produced as an N-oxide, e.g., pyrimidinyl N-oxide.

In some embodiments, "heteroaryl ", wherein the heteroatom is an N atom in the ring, is defined as a nitrogen containing heteroaryl. Nitrogen containing heteroaryl groups also include those in which the N heteroatoms are formed with N-oxides, such as pyridyl N-oxide.

Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridyl N-oxide; Pyrazinyl; Pyrimidinyl, pyrazolyl; Imidazolyl; Oxazolyl; Isoxazolyl; Thiazolyl; Isothiazolyl; Thiadiazolyl; Tetrazolyl; Triazolyl; Thienyl; Furyl; Pyranyl; Pyrrolyl; Pyridazinyl; Benzo [d] thiazolyl, benzodioxolyl such as benzo [d] [1,3] dioxolyl; Benzoxazolyl, such as benzo [d] oxazolyl; Imidazopyridyl, such as imidazo [1,2-a] pyridyl; Triazolopyridyl such as [1,2,4] triazolo [4,3-a] pyridyl and [1,2,4] triazolo [1,5-a] pyridyl; Indazolyl, 2H-indazolyl; Pyrrolopyrimidinyl such as pyrrolo [3,4-d] pyrimidinyl, 7H-pyrrolo [2,3-d] pyrimidinyl; Pyrazolopyrimidinyl such as pyrazolo [1,5-a] pyrimidinyl tetrazolopyridyl, such as tetrazolo [1,5-a] pyridyl; Benzothienyl; Benzofuryl; Benzoimidazolinyl; Indolyl; Indolinyl; Furinyl, such as 9H-purinyl and 7H-purinyl; Quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl, and the like.

 Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyrrolyl; Pyrazolyl; Imidazolyl; Pyridyl; Pyrazinyl; Pyrimidinyl, pyrimidinyl N-oxide; Pyridazinyl; Pyrrolopyrimidinyl such as pyrrolo [3,4-d] pyrimidinyl, 7H-pyrrolo [2,3-d] pyrimidinyl; Furinyl, such as 9H-purinyl and 7H-purinyl; Quinolinyl; Indolyl; And indazolyl.

As used herein, "hydroxyl" refers to the -OH radical.

As used herein, "mercapto" refers to a -SH radical.

As used herein, "oxo" denotes a = O radical.

As used herein, "carboxyl" refers to a -C (O) -OH radical.

As used herein, "cyano" refers to a -CN radical.

When the structural formula includes an " asterisk (*) ", the compound represented by this structural formula is a chiral compound, that is, a compound of R-configuration or S-configuration. The arrangement of the compounds may be determined using various analytical techniques, for example, single crystal X-ray crystallography and / or optical polarization measurements according to conventional protocols by those skilled in the art.

As used herein, the term "optional" or "optionally" means that a subsequently described substitution pattern, event, or circumstance may or may not occur, . For example, "optionally substituted alkyl" includes both "unsubstituted alkyl" and "substituted alkyl ", as defined herein. Those skilled in the art will appreciate that for any functional group containing one or more substituents, it is believed that such functional groups are stereostructically unrealistic, chemically inaccurate, can not actually be synthesized, and / or are not intended to introduce any inherently unstable substitution or substitution pattern .

As used herein, the term " substituted "or" substituted with "refers to the replacement of at least one hydrogen on the designated atom or group of functionalities with one or more functional groups selected from the corresponding functional groups of the substituent, It should not exceed the valence. If the substituent is oxo (i.e., = O), then two hydrogens on the single atom are replaced by oxo. The combination of substituents and / or modifications can only be allowed when such a combination produces a chemically correct and stable compound. A chemically correct and stable compound means a compound which is sufficiently resistant to separation even from the reaction mixture in which the chemical structure of the compound can be identified and which is sufficiently resistant to undergo subsequent formulations in the form of an agent having at least one practical use &Lt; / RTI &gt;

Unless otherwise indicated, the substituent is termed the core structure. For example, when (cycloalkyl) alkyl is presented as a possible substituent, it should be understood that the point of attachment of this substituent to the core structure is at the alkyl moiety.

As used herein, the term "substituted with one or more substituents" refers to the replacement of one or more hydrogens on a designated atom or functional group with one or more functional groups independently selected from the corresponding functional group of the substituent. In some embodiments, "substituted with one or more substituents" means that the designated atom or group is substituted with one, two, three or four substituents independently selected from the corresponding functional group of the substituent.

It will be understood by one of ordinary skill in the art that any of the compounds of formula (I) may contain one or more chiral centers and thus exist in two or more stereoisomeric forms. Racemates of these isomers, individual isomers and mixtures enriched in one enantiomer, diastereoisomers with two chiral centers, and mixtures in which the specific diastereoisomers are partially enriched are included within the scope of the present invention . POSITA will understand that the present invention encompasses both individual stereoisomers (e. G., Enantiomers), racemic mixtures, or partially resolvable mixtures of compounds of formula (I) and, suitably, individual tautomers.

In other words, in some embodiments, the invention provides compounds that include the purity of the various stereoisomers, i.e., the diastereomer or enantiomeric purity, as the various "ee" or "de". In some embodiments, the compound of formula (I) (eg, as described herein) is at least 60% ee (eg, 60%, 65%, 70%, 75%, 80%, 85% 98%, 99%, 99.5%, 99.9% ee, or a range between these enumerated values). In some embodiments, the compound of formula (I) (e.g., as described herein) is greater than 99.9% ee and up to 100% ee. Lt; / RTI &gt; enantiomeric purity. In some embodiments, the compound of formula (I) (eg, as described herein) is at least 60% de (eg, 60%, 65%, 70%, 75%, 80%, 85% And a range of degrees of diastereomeric purity, such as%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of greater than 99.9% de.

으로 정의하며, 여기서 R 및 S는 혼합물내의 거울상 이성질체 각각의 몰 또는 중량 비율을 나타내고 R + S = 1 이다. 키랄 물질의 광학 회전에 관한 지식에 따르면, 거울상 이성질체 잉여 백분율은 ([a]obs/[a]max)*100과 같이 정의되고, 여기서 [a]obs는 거울상 이성질체 혼합물의 광학 회전이며, [a]max는 순수 거울상 이성질체의 광학 회전이다.The term " enantiomeric excess "or" ee "refers to how much one enantiomer is present relative to the other components. In mixtures of R and S enantiomers, the percentage of enantiomeric excess is

, Where R and S represent the molar or weight ratio of each enantiomer in the mixture and R + S = 1. [A] obs / [a] max) * 100, where [a] obs is the optical rotation of the enantiomer mixture and [a] obs is the optical rotation of the enantiomer mixture ] max is the optical rotation of the pure enantiomer.

와 같이 정의되고, 여기서 D1 및 D2는 혼합물내의 부분입체 이성질체 각각의 몰 또는 중량비율이며, D1 + D2 = 1이다.The term " diastereomeric residue "or" de "refers to how much one diastereomer is present relative to the other components and is defined analogously to the case of the enantiomeric surplus. Thus, for mixtures of diastereoisomers D1 and D2, the diastereomeric excess percentage

Where D1 and D2 are the molar or weight ratio of each of the diastereomers in the mixture, and D1 + D2 = 1.

The diastereoisomeric and / or enantiomeric excess amounts can be determined by various analytical techniques including NMR spectroscopy, chiral column chromatography and / or optical polarization measurements according to conventional protocols recognized by POSTA.

The racemate may be used as is or may be resolved into its respective individual isomer. Upon degradation, a stereochemically pure compound or a mixture enriched in one or more isomers may be provided. Isomer separation methods are well known in the art and include physical methods such as chromatography using chiral adsorbents ( cf. Allinger NL and Eliel EL in "Topics in Stereochemistry" , Vol. 6, Wiley Interscience, 1971). Each isomer may be prepared in chiral form from a chiral precursor. Alternatively, a diastereomeric salt such as an individual enantiomer such as 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid or the like is formed with chiral acid, The individual isomers can be chemically separated from the mixture by fractional crystallization of the salt, vitrification of one or both of the cleaved bases, and optionally, repeating the above process, so that substantially any one or both of them That is to say in the form of an optical purity of at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% The desired stereoisomer can be obtained. Alternatively, as known to POSIT, the chiral auxiliary may be chemically removed to provide the pure enantiomer, followed by covalent attachment of the racemate to the chiral compound (adjuvant) to afford the diastereomer Lt; / RTI &gt;

Also provided are pharmaceutically acceptable salts of the compounds of formula (I), such as the pharmaceutically acceptable salts of certain compounds described hereinafter and exemplified herein, and methods of using such salts.

"Pharmaceutically acceptable salt" refers to a salt of a free acid or base of a compound of formula (I), which is non-toxic, bioavailable, or a biocompatible salt to be administered to a subject. See, for example, SM Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use , Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002).

"Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with compounds of formula (I) and inorganic acids such as hydrogen chloride, hydrogen bromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate and the like; And acid addition salts formed with organic acids such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2- Hydroxyethylsulfonic acid salts, benzoic acid salts, salicylic acid salts, stearic acid salts and the like; And a salt with an alkane-dicarboxylic acid having the general formula HOOC- (CH ₂ ) _n -COOH, wherein n is from 0 to 4, and the like. In addition, "pharmaceutically acceptable salts" refers to salts of compounds of formula (I) that contain an acid moiety and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium &Lt; / RTI &gt; The molar ratio of compounds of formula (I) to acids or cations in the resulting pharmaceutically acceptable salts is, but is not limited to, 1: 1, 1: 2, 1: 3, and 1: 4.

In addition, when the compounds described herein are obtained in the form of an acid addition salt, a free base can be obtained by basifying a solution of the acid addition salt. Conversely, when the product is a free base, the free base is dissolved in an appropriate solvent and the acid is treated with an acid according to a conventional method for preparing an acid addition salt from a base compound to give an acid addition salt, Acid addition salts can be prepared. POSITA will recognize a variety of synthetic methods that can be used without undue experimentation to produce non-toxic pharmaceutically acceptable acid addition salts.

The term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap solid solvent molecules at a defined molar ratio, thereby forming solvates. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with materials in which the water retains the molecular state, i.e., the form of H ₂ O, and by this combination, one or more hydrates, such as, for example, anhydride, monohydrate, In addition, various hydrates can be formed.

As used herein, the terms "functional group "," radical ", and "moiety" are used interchangeably and refer to a functional group or fragment of a molecule attached to another fragment of a molecule.

The term "active ingredient" is used to refer to a chemical having a physiological activity. In some embodiments, "active ingredient" is a chemical that has pharmaceutical utility. The pharmacological activity practicable in the United States can be established in vitro or in vivo according to appropriate preclinical analysis. Adequate pharmacological activity to accommodate regulatory agencies such as the US FDA is a higher standard than preclinical studies. Such high pharmacological activity criteria can generally establish these criteria only through appropriate and successful randomized double eyelid control clinical trials for humans, at a level of unpredictable success as a result of prior clinical studies.

The term " treating ", "treating ", or" treating "a disease or disorder in the context of achieving therapeutic efficacy includes treating a condition or disorder predisposing to a disease or disorder, (I) and / or a pharmaceutically acceptable salt thereof as described herein for the manufacture of a medicament for the treatment, prevention, amelioration, alleviation, amelioration, alteration, Refers to administration to a human subject having a subject, for example, a disease or disorder, a symptom of the disease or disorder, or a symptom of susceptibility to disease or disorder.

The term " treating ", "contacting" or "reacting " in the context of a chemical reaction refers to the addition or mixing of two or more reagents under appropriate conditions to produce the product and / or the desired product. The reaction to produce the product and / or the desired product need not result directly from the combination of these two reagents initially added, there being at least one intermediate produced in the mixture, and finally the product and / &Lt; / RTI &gt; and / or form the desired product.

As used herein, the term "effective amount" refers to the amount or dose of a PI ₃ K inhibitor sufficient to cause a therapeutic efficacy, generally adjusted by PI ₃ K activity, in a patient in need of treatment of the disease or disorder. The effective amount or effective dose of the active ingredient herein is determined by methods such as modeling, dose escalation studies or clinical trials, and various factors such as the route or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, The patient's past or current treatment status, the health condition of the subject, the drug responsiveness, and the decision of the primary care physician. In other words, determining the effective dose is usually unpredictable in the United States through preclinical studies. In fact, doses can not be fully predicted when new, unforeseeable dosing regimens are developed after dosing is initially used in randomized double eyelid control clinical trials.

Experimental doses range from about 0.0001 to about 200 mg of active agent per kilogram body weight of the subject per day, such as from about 0.001 to 100 mg / kg / day, in single or multiple dose units (e.g., BID, TID, QID) Day, about 0.01 to 35 mg / kg / day, or about 0.1 to 10 mg / kg / day. In the case of a person weighing 70 kg, an exemplary range of the appropriate dose is about 0.05 to about 7 g / day or about 0.2 to about 5 g / day. Once the patient's disease or disorder has improved, the dose can be adjusted and managed. For example, the dose, the number of doses, or both can be reduced to a level that maintains the desired therapeutic effect as a function of symptom. Of course, treatment can be stopped if the symptoms have been relieved to an appropriate level. However, recurrence of symptoms on the patient side may require long-term intermittent treatment.

The term "inhibiting" or "inhibiting" refers to a decrease in the activity of a physiological activity or a process. The term "PI ₃ K inhibitory activity" is actually the pharmaceutical activity of the purposes of this disclosure, the formula (I) compound and / or as a direct or indirect response to the pharmaceutically acceptable salts there described herein PI ₃ K of Activity, which is a relative effect on PI ₃ K activity in the absence of the compound of formula (I) and / or its pharmaceutically acceptable salts. The reduction in such activity may be determined by the fact that the compound of formula (I) and / or its pharmaceutically acceptable salts described herein directly interacts with PI ₃ K, or the compound of formula (I) and / or its pharmaceutically acceptable Since the salt interacts with one or more other factors and this affects PI ₃ K activity. For example, other factors that when the compound and / or its pharmaceutically acceptable salt described herein for formula (I) is present, bonded directly to the PI ₃ K, or lowering the PI ₃ K activity (directly or indirectly) Or reduce the PI ₃ K activity by reducing (directly or indirectly) the amount of PI ₃ K present in the cell or organ.

As used herein, the term "subject" refers to mammals and non-mammals. Mammalia refers to members of the mammal, including, but not limited to, humans; Non-human primates, such as chimpanzees and other apes and monkey species; Cattle, horses, sheep, goats and pigs; Rabbits, livestock such as dogs and cats; Rats, laboratory animals including rodents such as mice and guinea pigs, and the like. Examples of non-mammalian animals include, but are not limited to, birds and the like. The term "subject" does not specify a particular age or sex. In some embodiments, the subject is a human.

Generally, as used herein, the term " about "refers to a regression of the numerical values before and after the specified value with a 20% variation.

The technical and scientific terms used herein without any specific definition have the meaning commonly understood by POSITA in the field to which the present invention pertains.

One embodiment of this disclosure is directed to a compound of formula (I)

And / or a pharmaceutically acceptable salt thereof, and / or a solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein

Ar is aryl or heteroaryl, each of which is deuterium, halo, -CN, -OH, -SH, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl , -O (C _1-6 alkyl), - (C _{1-6 alkyl) OH, -NH 2, -NH (} C 1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl ) And -S (O) ₂ (C _1-6 alkyl);

W is heteroaryl and -N (R ₃₎ selected from heteroaryl, and wherein the heteroaryl group is halo, -CN, -OH, -SH, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl carbonyl, C _1-6 haloalkyl, -O (C ₁ - ₆ alkyl), - (C ₁ - _{6 alkyl) OH, -NH 2, -NH (} C 1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl), -COOH, -C (O) NH 2, -C (O) NH (C 1-6 alkyl), -C (O) N ( C 1-6 alkyl) (C _{1-6 alkyl), - SO 2 (C 1} - 6 alkyl), phenyl and 5-or 6-membered is optionally substituted with one or more functional groups selected from heteroaryl; As substituents of W, where phenyl or 5-or 6-membered heteroaryl are each halo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -O (C ₁ - ₆ alkyl) , - (C _1-6 alkyl) OH, -NH ₂ , -NH (C _1-6 alkyl), and -N (C _1-6 alkyl) (C _1-6 alkyl) ;

R ₁ is independently selected from H, halo, -CN, C _1-6 alkyl, C _1-6 haloalkyl, - (C _1-6 alkyl) OH, - (C _1-6 alkyl) O (C _1-6 alkyl And C _2-6 alkynyl;

R ₂ is H, C _1-6 alkyl, and C ₃ - ₈ is selected from cycloalkyl, each of which, except H, halo, -CN, C _1-6 alkyl, one selected from the group consisting of C _1-6 haloalkyl, and -OH Optionally substituted by at least one functional group;

R ₃ is H or C _1-6 alkyl;

m is 1 or 2;

Expression, and (I) compound In some embodiments W is heteroaryl containing heteroaryl or -N (R ₃₎ a nitrogen-containing nitrogen as in the case of a nitrogen containing heteroaryl is halo, -CN, -OH, -SH, C 1 _-6 alkyl, C _1-6 haloalkyl, -O (C ₁ - ₆ alkyl), - (C ₁ - _{6 alkyl) OH, -NH 2, -NH (} C 1-6 alkyl), -N (C _{1 -6} alkyl) (C _1-6 alkyl), -COOH, -C (O) NH 2, -C (O) NH (C 1-6 alkyl), -C (O) N ( C 1-6 alkyl) (C _1-6 alkyl), -SO ₂ (C _1-6 alkyl), phenyl and 5- or 6-membered heteroaryl; It said phenyl or 5-or 6-membered heteroaryl are each halo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -O as substituents of W (C ₁ - ₆ alkyl) , - (C _1-6 alkyl) OH, -NH ₂ , -NH (C _1-6 alkyl), and -N (C _1-6 alkyl) (C _1-6 alkyl) .

In some embodiments of the compounds of formula (I), W is nitrogen-containing heteroaryl or -N (R ₃ ) nitrogen-containing heteroaryl wherein the nitrogen-containing heteroaryl is fluoro, chloro, bromo, -CN, -OH , -SH, C _1-6 alkyl, C _1-6 haloalkyl, -NH _2, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl), -COOH , and optionally substituted with -C (O) NH _2, phenyl and a 5- or 6-membered one or more functional groups selected from heteroaryl; Is optionally substituted by one or more functional groups selected from - (C _{1 6} alkyl) as a substituent of the W-phenyl, or 5- or 6-membered heteroaryl are each halo, -OH, C _1-6 alkyl and -O.

In some embodiments of compounds of formula (I), the nitrogen-containing heteroaryl is pyrimidinyl, pyrrolopyrimidinyl, and pyridinyl.

In some embodiments of compounds of formula &lt; RTI ID = 0.0 &gt; (I) &lt;

It is selected, each of which is fluoro, chloro, bromo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -NH _2, -NH (C _1-6 alkyl) from , -N (C _1-6 alkyl) (C _1-6 alkyl), -COOH, -C (O) NH 2, C (O) NH (C 1-6 alkyl), phenyl and 5-or 6-membered Optionally substituted with one or more functional groups selected from heteroaryl; It said phenyl or 5-or 6-membered heteroaryl are each halo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -O as substituents of W (C ₁ - ₆ alkyl) , - (C _1-6 alkyl) OH, -NH ₂ , -NH (C _1-6 alkyl), and -N (C _1-6 alkyl) (C _1-6 alkyl) .

In some embodiments of compounds of formula (I), W is

And, which is fluoro, chloro, bromo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -NH _2, -NH (C _1-6 alkyl), -N ( Optionally substituted with one or more functional groups selected from C _1-6 alkyl) (C _1-6 alkyl), -COOH, -C (O) NH ₂ , phenyl and 5- or 6-membered heteroaryl; Is optionally substituted by one or more functional groups selected from - (C _{1 6} alkyl) as a substituent of the W-phenyl, or 5- or 6-membered heteroaryl are each halo, -OH, C _1-6 alkyl and -O.

In some embodiments of compounds of formula (I), W is

It is selected from, each of _{chloro, -CN, -NH 2, -NH (} C 1-6 alkyl), -COOH, -C (O) NH 2, phenyl, pyridyl, oxadiazolyl, pyrazolyl, and tetra Optionally substituted by one or more functional groups selected from the group consisting of halo; Said phenyl, pyridyl, oxadiazolyl, pyrazolyl, or tetrazole each day halo, -OH, C _1-6 alkyl, and -O - is optionally substituted by one or more functional groups selected from (C _{1 6} alkyl).

In some embodiments of compounds of formula (I), W is

And, it _{chloro, -CN, -NH 2, NH (} C 1-6 alkyl), -COOH, -C (O) NH 2, or more of phenyl, pyridyl, oxadiazolyl, one selected from the group consisting of pyrazolyl and tetrazolyl Lt; / RTI &gt; Said phenyl, pyridyl, oxadiazolyl, pyrazolyl, or tetrazole each day halo, -OH, C _1-6 alkyl, and -O - is optionally substituted by one or more functional groups selected from (C _{1 6} alkyl).

In some embodiments of compounds of formula (I), Ar is phenyl, naphthyl, pyridyl, pyrazolyl, quinolyl, thienyl, benzothiazolyl, indolyl and 2,3-dihydro- deoxy selected from carbonyl, each of which is deuterium, halo, -CN, C _1-6 alkyl, - (C _1-6 alkyl) OH, C _1-6 haloalkyl, and -S (O) ₂ (C _{1- 6} alkyl). &Lt; / RTI &gt;

In some embodiments of the compounds of formula (I), Ar is phenyl or pyridyl, each of which is optionally substituted with one or more functional groups selected from halo, -CN and C _1-6 haloalkyl.

In some embodiments of the compounds of formula (I), Ar is phenyl or pyridyl, each of which is optionally substituted with one or more halo, and in particular is optionally substituted with one or more fluoro.

In some embodiments of compounds of formula (I), R ₁ is independently selected from H, halo, -CN and C _1-6 alkyl.

In some embodiments of the compounds of formula (I), R ₂ is C _1-6 alkyl, especially C _1-4 alkyl, further methyladecyl.

In some embodiments of compounds of formula (I), R &lt; ₃ &gt;

In some embodiments of compounds of formula (I), m is 1.

In some embodiments of compounds of formula (I), formula (I) is formula (I-1).

In some embodiments of compounds of formula (I-1), W is nitrogen containing heteroaryl or -N (R ₃ ) nitrogen containing heteroaryl wherein said nitrogen containing heteroaryl is fluoro, chloro, bromo, -CN , -OH, -SH, C _1-6 alkyl, C _1-6 haloalkyl, -NH _2, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl) , Phenyl and 5- or 6-membered heteroaryl.

In some embodiments of compounds of formula (I-1), said nitrogen-containing heteroaryl is selected from pyrimidinyl, pyrrolopyrimidinyl and pyridinyl.

In some embodiments of compounds of formula (I-1), W is

It is selected, each of which is fluoro, chloro, bromo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -NH _2, -NH (C _1-6 alkyl) from , -N (C _1-6 alkyl) (C _1-6 alkyl), phenyl and 5- or 6-membered heteroaryl.

In some embodiments of compounds of formula (I-1), W is

It is selected from, each of which is optionally substituted by one or more functional groups selected from -CN, -NH _2, and tetrazolyl.

In some embodiments of compounds of formula (I-1), W is

And, which is fluoro, chloro, bromo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -NH _2, -NH (C _1-6 alkyl), -N ( C _1-6 alkyl) (C _1-6 alkyl), phenyl and 5- or 6-membered heteroaryl.

In some embodiments of compounds of formula (I-1), W is

And, which it is optionally substituted by one or more functional groups selected from -CN, -NH _2, and tetrazolyl.

In formula (I-1) portion of the compound embodiments, Ar is phenyl, naphthyl, is selected from pyridyl, pyrazolyl, quinolyl, thienyl and benzothiazolyl, each of which is halo, -CN, C _1- It is optionally substituted by (C _1-6 alkyl) OH, and at least one functional group selected from a C _{1-6 haloalkyl-6} alkyl.

In addition, the compounds selected from the compounds (1) to (9) and (11) to (82) as listed in the experimental section and / or a pharmaceutically acceptable salt thereof are provided.

In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., Thereby providing a pharmaceutical composition.

In another aspect, the compounds of formula (I) in an effective amount (e.g., any compound described herein) and / or their pharmaceutically acceptable salts and PI ₃ of internal or external PI comprising contacting a K ₃ K inhibitory &Lt; / RTI &gt;

In another aspect, there is provided a pharmaceutical composition comprising an effective amount of a compound of formula (I) (e.g., any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient effective to inhibit PI ₃ K activity It provides an internal or external PI ₃ K active suppression method which comprises contacting a pharmaceutical composition with PI ₃ K containing (e.g., pharmaceutical acceptable carrier).

In yet another aspect, a method of administering to a subject in need of treatment a compound of formula (I) (e.g., any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit PI ₃ K of the subject A method of treating a disease responsive to PI ₃ K inhibition of said subject.

In another aspect, treating a compound of a required target a target of PI ₃ K formula (I) in an amount effective to inhibit (e. G., Any of the compounds described herein) and / or its pharmaceutically acceptable salts and also at least There is provided a method of treating a disease responsive to PI ₃ K inhibition of the subject, comprising administering a pharmaceutical composition comprising one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

In another aspect, by inhibiting PI ₃ K of the target the PI ₃ The compounds of formula (I) for use in the treatment of diseases that respond to inhibition of K (for example, any of the compounds described herein) and / or present Lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salts thereof.

In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and / or its pharmaceutical acceptance described herein, which is used in the manufacture of a medicament for treating a disease responsive to inhibition of PI ₃ K. Lt; RTI ID = 0.0 &gt; salts.

In some embodiments, the disease responsive to inhibition of the PI ₃ K is an inflammatory disease, autoimmune disease or cancer.

In some embodiments, the inflammatory disease or autoimmune disease is selected from rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus, systemic lupus erythema, psoriasis and multiple sclerosis.

In some embodiments, the cancer is a solid cancer or a blood cancer selected from leukemia, multiple myeloma (MM), and lymphoma.

In some embodiments, the leukemia is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).

In some embodiments, the lymphoma is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), coccygeal lymphoma (MCL), vesicular lymphoma, B-cell lymphoma, T-cell lymphoma and extensive B-large cell lymphoma Is selected.

In another aspect, there is provided a compound of formula (II) and / or a salt thereof, and / or a racemic mixture or enantiomer thereof, which comprises preparing a compound of formula (I) .

Wherein Ar and R &lt; ₂ &gt; are as defined in formula (I).

In some embodiments, the compound of formula &lt; RTI ID = 0.0 &gt; (II) &lt; / RTI &

.

Synthesis method of the disclosed embodiment

The compounds of formula (I) described herein and their pharmaceutically acceptable salts described herein may be synthesized from starting materials commonly used according to methods known in the art, along with the disclosure of the present application. The following scheme illustrates the general method of preparation of some of the compounds described herein.

Scheme (I)

As shown in Scheme (I) above, the compound of formula (i-1) reacts with N, O -dimethylhydroxylamine to provide the amide compound of formula (i-2). Reaction of the compound of formula (i-2) with MH provides the compound of formula (i-3) and is reacted with a compound of formula (ArB (OH) ₂ ) Suzuki coupling to form a compound of formula (i-4). Pd- catalyzed CC linking reaction is _{Pd (OAc) 2, Pd (} dppf) Cl 2, Pd (PPh 3) 4 or Pd ₂ (dba) _3, using a catalyst such as suitable, such as DMF, ACN, THF or DMSO It may be carried out in a suitable base, such as a polar solvent and _{TEA, DIPEA, Cs 2 CO 3} , KOAc. Next, the following reaction is carried out:

1) Formation of a compound of formula (i-5) by reaction of a compound of formula (i-4) with a Grignard reagent (alkylmagnesium halide) under suitable conditions which yields ( R ) -2-methylpropane- Followed by a subsequent reaction in the presence of a condensing reaction with an amide and an appropriate reducing reagent to form a compound of formula (i-7); or

2) Reduction of the compound of formula (i-4) in the presence of a suitable reducing reagent to form a compound of formula (i-5 ') which undergoes a condensation reaction with ( R ) -2-methylpropane- And subsequent reaction with a Grignard reagent (alkylmagnesium halide) under suitable conditions to form a compound of formula (i-7).

The compound of formula (i-7) is deprotected to form the compound of formula (i-8), which is crystallized with chloroacetaldehyde in the presence of a base such as NaHCO ₃ to form the compound of formula (i-9) Followed by deprotecting it to form a compound of the formula (i-10). The compound of formula (i-10) reacts with Cl-V in the presence of a base such as DIPEA under appropriate conditions to form a compound of formula (i-11), which undergoes further reaction, To provide a compound of formula (I).

Reaction formula (II)

As shown in Scheme (II) above, the compound of formula (i-1) reacts with N, O -dimethylhydroxyamine to provide the amide compound of formula (i-2). The compound of formula (i-2) is reacted with MH to form a compound of formula (i-3). Then, the following reaction is carried out:

1) The compound of formula (i-3) is reduced in the presence of a suitable reducing agent to form a compound of formula (i-4), which under appropriate conditions after condensation with ( R ) -2-methylpropane- Subsequent reaction with a Grignard reagent (alkylmagnesium halide) to form a compound of formula (i-6); or

2) to form a compound of the reaction so as to carry the reagent (alkyl magnesium halide), the compound of formula (i-3) under appropriate conditions to formula (i-4 '), which (R) -2-methylpropane-2- After the condensation reaction with the sulfinamide, the compound of the formula (i-6) is subjected to a subsequent reaction in the presence of a suitable reducing reagent.

The compound of formula (i-6) forms a compound of formula (i-8) by deprotection and protection reaction, which is cyclized with chloroacetaldehyde in the presence of a base such as NaHCO ₃ to give the compound of formula (i- To form a compound. The compound of formula (i-9) can be converted to a compound of formula (I-9) in the presence of a suitable palladium catalyst such as Pd ₂ (dba) ₃ in standard stille coupling or Suzuki coupling conditions and an appropriate ligand such as X- ) ₂ (wherein Ar is as defined herein) to form a compound of formula (i-10), which provides a compound of formula (i-11) via deprotection. The compound of formula (i-11) is reacted with Cl-V in the presence of a base such as DIPEA under suitable conditions to form a compound of formula (i-12), which under the appropriate conditions further reaction (s) To give the compound of formula (I).

The compounds thus obtained can modify their terminal positions to provide the desired compound. Synthetic chemical modification techniques are described, for example, in the following known literature (R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3 ^rd Ed. John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and subsequent editions thereof.

Prior to use, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof described herein may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

Pharmaceutical composition and practical use

The compounds of formula (I) (e.g., any of the compounds described herein) and / or pharmaceutically acceptable salts thereof described herein formulate pharmaceutical compositions either alone or in combination with one or more additional active ingredients. The pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein; And (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

A pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredients of the composition (and, in some embodiments, can stabilize the active ingredient), and is not deleterious to the subject to be treated. For example, solubilizing agents such as cyclodextrins (which form specific complexes and higher solubility complexes with the compounds of formula (I) and / or their pharmaceutically acceptable salts described herein) Can be utilized as a pharmaceutical excipient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate and pigments such as D and C Yellow # 10, and the like. Suitable pharmaceutical acceptable carriers are described in the literature (Remington ' s Pharmaceutical Sciences, A. Osol, Fundamental Reference in the Field).

Pharmaceutical compositions comprising a compound of formula (I) (e.g., any of the compounds described herein) and / or a pharmaceutically acceptable salt thereof as described herein may be administered in a variety of known ways, including oral, topical, rectal, It can be administered by spray, or through a graft device. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intra-synovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions described herein may be prepared in the form of tablets, capsules, pouches, dragees, powders, granules, tablets, reconstitutable powders, liquid preparations or suppository forms. In some embodiments, the pharmaceutical composition comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof is formulated in the form of intravenous infusion, topical administration or oral administration.

Oral compositions include, but are not limited to, any oral dosage form including tablets, capsules, emulsions, aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. Diluents useful in capsule-type oral administration include lactose and dried cornstarch. When an aqueous suspension or emulsion is orally administered, the active ingredient may be suspended or dissolved in an oily phase in combination with an emulsifying agent or a suspending agent. Sweetening agents, flavoring agents or coloring agents may be added if desired.

In some embodiments, the compound of formula (I) and / or a pharmaceutically acceptable salt thereof is administered to a tablet at 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, , 150, 200, 250, 300, 400 and 500 mg. In some embodiments, the compound of formula (I) and / or a pharmaceutically acceptable salt thereof is administered to a capsule at a dosage of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, , 150, 200, 250, 300, 400 and 500 mg.

The sterile injectable composition (e.g., aqueous or oily suspensions) may be formulated according to the known art using suitable dispersing or wetting agents (e. G., Tween 80, etc.) and suspending agents. The sterile injectable-type intermediate may be a solution which is dissolved in a sterile injectable solution or suspension added to a non-toxic parenterally acceptable diluent or solvent, for example, 1,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. They are also commonly used as sterile, nonvolatile inducing solvents or suspending media (e.g., synthetic mono- or di-glycerides). Fatty acids, such as oleic acid and its derivatives, are useful in the preparation of intermediates for injectables, such as natural pharmaceutical acceptable salts, especially in polyoxyethylated form, such as olive oil or castor oil. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersing agents.

Inhalation compositions may be formulated according to techniques well known in the art of pharmaceutical formulation and may also be prepared using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other known solubilizers, It may be prepared in the form of a solution dissolved in saline.

The composition for topical administration may be formulated in the form of an oil, a cream, a lotion, an ointment or the like. Suitable carriers for this composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and higher molecular weight alcohols (greater than C12). In some embodiments, the pharmaceutically acceptable carrier is a carrier in which the active ingredient is dissolved. Emulsifiers, stabilizers, wetting agents and antioxidants may also be included with the agents that impart color and aroma if desired. Transdermal permeation enhancers may also be used in these topical dosage forms. Examples of such an improving agent can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

The cream may be formulated using a mixture of mineral oil, self-emulsifying beeswax and water and the active ingredient dissolved in a small amount of oil, such as almond oil, is mixed into the mixture. Examples of such creams include about 40 parts by weight of water, about 20 parts of beeswax, about 40 parts of mineral oil, and about 1 part of almond oil. Ointment is formulated by mixing the active ingredient with a warm soft paraffin in a vegetable oil, for example, a solution in an almond oil, and cooling the mixture. Examples of such ointments include ointments containing about 30 wt% almond oil and about 70 wt% white soft paraffin oil.

PI ₃ Kδ. For active inhibition, the proper utility of a compound of formula (I) and / or its pharmaceutically acceptable salts described herein may be assessed using appropriate in vitro assays. The compounds of formula (I) and / or their pharmaceutically acceptable salts described herein may be further studied through in vivo analysis for additional practical usefulness in the treatment of cancer or autoimmune diseases. For example, the compound of formula (I) and / or its pharmaceutically acceptable salts described herein may be administered to an animal having a cancer or autoimmune disease (e.g., a mouse model) to analyze its therapeutic effect. Assuming that the pre-clinical test results are successful, the above results can be projected to the dosage range and route of administration of an animal subject, such as a human.

The compounds of formula (I) (e.g., any of the compounds described herein) and / or pharmaceutically acceptable salts thereof disclosed herein have sufficient preclinical experimental utility, which may include, for example, It is worthy of use in clinical trials to prove preventive effects.

As used herein, the term "cancer" refers to a cell disorder characterized by uncontrolled cell growth, decreased cell differentiation, inappropriate ability to attack surrounding tissue, and / or ability to establish new growth at the heterologous site . The term "cancer" includes, but is not limited to, solid tumors and blood cancers. The term "cancer " encompasses diseases of the skin, tissues, organs, bones, cartilage, blood and blood vessels. The term "cancer" also includes primary cancer and metastatic cancer.

Non-limiting examples of solid tumors include pancreatic cancer; Bladder cancer; Rectal cancer; Breast cancer including metastatic breast cancer; Prostate cancer, including androgen-dependent and androgen-independent prostate cancer; Kidney cancer, including, e.g., metastatic kidney cell carcinoma; Hepatocellular carcinoma; Lung cancer, including, for example, non-small cell carcinoma (NSCLC), bronchoalveolar carcinoma (BAC), and pheosis carcinoma; Ovarian cancer including advanced epithelial cancer or primary peritoneal cancer; Cervical cancer; Gastric cancer; Esophagus cancer; Head and neck cancer including squamous cell carcinoma of head and neck; Skin cancer, including malignant melanoma; Neuroendocrine cancer, including metastatic neuroendocrine tumors; Glioma, malignant brain glioma, adult glioblastoma brain cancer and brain tumors including adult malignant neoplasm: bone cancer; Soft tissue sarcoma; And thyroid cancer.

Non-limiting examples of blood cancers include acute myelogenous leukemia (AML); Chronic myelogenous leukemia (CML) including accelerated CML and CML capsaicin (CML-BP); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma; Non-Hodgkin's lymphoma (NHL), including vesicular lymphoma and vesicular lymphoma; B-cell lymphoma; T-cell lymphoma; Multiple myeloma (MM); Valtendrome macroglobulinemia; (MDS), including refractory anemia (RA), refractory anemia (RARS) with ring iron fibrillation, refractory anemia (RAEB) and RAEB (RAEB-T) during transformation; And myeloproliferative syndrome and the like.

In some embodiments, exemplary blood cancers include leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML); Multiple myeloma (MM); Cell lymphoma (MCL), vesicular lymphoma, B-cell lymphoma, T-cell lymphoma and extensive B-cell lymphoma (DLBCL), and the like.

The term " inflammatory disease "refers to a pathological condition in which inflammation occurs and is usually caused by neutrophil chemotaxis. Examples of such diseases include inflammatory skin diseases including psoriasis and atopic skin; Systemic sclerosis and systemic sclerosis; Reactions associated with inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis); Ischemic reperfusion injury including myocardial ischemic conditions such as surgical tissue reperfusion injury, myocardial infarction, cardiac arrest, post-cardiac reperfusion and percutaneous transluminal coronary angioplasty shrinkage, stroke, and abnormal aortic bag; Secondary cerebral edema after stroke; Head trauma, hypovolemic shock; choke; Adult acute respiratory distress syndrome; Acute lung injury; Bae, Chee - Byung; Dermatomyositis; Polymyositis; Multiple sclerosis (MS); dermatitis; Meningitis; encephalitis; Uveitis; Osteoarthritis; Lupus nephritis; Autoimmune diseases such as rheumatoid arthritis (RA), Sjurgense syndrome, and vasculitis; Diseases involving leukocyte leaks; Central nervous system (CNS) secondary multiple organ trauma due to inflammatory disorders, sepsis or trauma; Alcoholic hepatitis; Bacterial pneumonia; Antigen-antibody complex mediated diseases including glomerulonephritis; blood poisoning; Rheumatoid arthritis; Immunopathological response to transplantation of tissue / organ; Inflammation of the lungs such as pleurisy, feverfever, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse common bronchiolitis, irritable interstitial pneumonia, idiopathic pulmonary fibrosis (IPF) and cystic fibrosis. Preferred subjects without limitation include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis, asthma, systemic lupus erythematosus, adult acute respiratory distress syndrome, , Psoriasis, chronic lung disease, graft versus host disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease, fever.

The compounds of formula (I) and / or the pharmaceutically acceptable salts described herein may be used to achieve beneficial therapeutic or prophylactic effects, for example, in subjects with autoimmune diseases.

The term "autoimmune disease" refers to a disease or disorder caused by and / or directed against an individual's own tissue or organ, its sequestration or expression, or the pathology therefrom. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), allergic arthritis, lupus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, , Asthma, idiopathic thrombocytopenic purpura, myeloproliferative disorders such as myelofibrosis, PV / ET (post-erythrocyte hypertension / essential thrombocythemia myelofibrosis).

In some embodiments, the inflammatory diseases and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic arthritis, asthma, lupus, systemic lupus erythematosis, psoriasis and multiple sclerosis.

In addition, the compounds of formula (I) (e.g., any of the compounds described herein) and / or pharmaceutically acceptable salts thereof disclosed herein may also be used in combination with additional active ingredients for the treatment of cancer, inflammatory diseases or autoimmune diseases have. The additional active ingredient may be coadministered independently of the compound of formula (I) and / or its pharmaceutically acceptable salts described herein, or incorporated into one of the components of the pharmaceutical composition according to the invention, for example, It can also be used as a form. In one exemplary embodiment, the additional active ingredient is a substance that is known or published to exert an effect in the treatment of a disease modulated by PI ₃ K activity, for example, other PI ₃ K modulators or other Is a compound that exhibits activity against a target. Such a combination agent may be administered in combination with a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, while enhancing efficacy (e. G., By including in the combination a compound that enhances the efficacy or efficacy of a compound of formula (I) and / / RTI &gt; and / or may reduce the side effects of the pharmaceutically acceptable salts thereof described herein or reduce the required dose.

Example

The following examples are for illustrative purposes only and are not intended to be limiting in any way. Unless otherwise noted, parts are parts by weight, temperatures are in degrees centigrade, and pressures are at or near atmospheric. All MS data were obtained according to Agilent 6120 and / or Agilent 1100. All reagents used herein, except intermediates, are commercially available. All compound names except reagents were written in Chemdraw 12.0.

The abbreviations used in the following examples are as follows:

ACN: acetonitrile

Boc: tert -Butoxycarbonyl

Boc ₂ O: di- t -butyl-dicarbonate

DAST: diethylaminosulfur trifluoride

DCM: dichloromethane

DEA: Diethylamine

DMF: N, N -dimethylformamide

DMA: Dimethylacetamide

DIBAL-H: Diisobutylaluminum hydride

DIPEA: N, N -diisopropylethylamine

EDCl: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc / EA: ethyl acetate

Et ₃ N: Triethylamine

HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'- tetra- methyluronium hexafluorophosphate

HBTU: O-benzotriazole- N, N, N ', N' -tetramethyl-uronium-hexafluoro-phosphate

HOAc: Acetic acid

HOBT: 1-hydroxybenzotriazole

ee: enantiomeric excess

mL: Milliliter

g: nanogram

mg: milligrams

ng: nanogram

mol: mol

mmol: millimolar

min: minutes

h: hour

mCPBA: 3-chloroperoxybenzoic acid

MeOH: methanol

NaH: Sodium hydride

NCS: N -chlorosuccinamide

NMP: N-methyl-2-pyrrolidone

PE: Petroleum ether

Pd (dppf) Cl ₂ : [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride

Pd ₂ (dba) ₃ : Tris (dibenzylideneacetone) dipalladium (0)

Pd (PPh _{3) 4:} tetrakis (triphenylphosphine) palladium (0)

PMB: p -methoxybenzyl

PPh ₃ : triphenylphosphine

THF: tetrahydrofuran

TFA: Trifluoroacetic acid

TFE: Trifluoroethanol

TsOH: 4-methylbenzenesulfonic acid

Xphos: 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl

Example 1

Synthesis of compounds (1) to (9) and (11) to (82)

Compound (1)

4-Amino-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

(A) 3-Chloro-6-hydroxypyridazine-4-carboxylic acid

가 될 때까지 염산으로 산성화 처리했다. 용액을 농축하고 이로부터 얻은 잔사를 플래시 컬럼 크로마토그래피 (H₂O/MeOH)로 정제하여 황색 고체 형태의 산물을 수득했다 (5.2 g, 수율 57%). MS (m/z): 175 [M+H]⁺ A solution of 3,6-dichloropyridazine-4-carboxylic acid (10 g, 51.8 mmol) in an aqueous solution of NaOH (2N, 200 mL) was refluxed overnight. After cooling to room temperature,

Lt; RTI ID = 0.0 &gt; acid. &Lt; / RTI &gt; The solution was concentrated and the resulting residue was purified by flash column chromatography (H ₂ O / MeOH) to give the product as a yellow solid (5.2 g, yield 57%). MS (m / z): 175 [M + H] &lt; ^{+ &}

(B) Methyl-3-chloro-6-hydroxypyridazine-4-carboxylate

To a solution of 3-chloro-6-hydroxypyridazine-4-carboxylic acid (5 g, 28.7 mmol) in MeOH (30 mL) was added concentrated H ₂ SO ₄ (1 mL). This solution was stirred at 100 ° C overnight. After cooling to room temperature, the reaction solution was concentrated and the resulting residue was purified by flash column chromatography (H ₂ O: MeOH = 100: 0 to 0: 100) to give a white solid product (5 g, 93%). MS (m / z): 189 [M + H] &lt; ^{+ &}

(C) Methyl 6-hydroxy-3-phenylpyridazine-4-carboxylate

N _2-dioxane (60 mL) contained in a flask under an atmosphere with methyl 3-chloro-6-hydroxy-pyridazin-4-carboxylate (5 g, 26.6 mmol), phenyl boric acid dissolved in H ₂ O (6 mL) ( Pd (dppf) Cl ₂ (1.08 g, 13.3 mmol) was added to a mixture of the above compound (6.49 g, 53.2 mmol) and KOAc (5.21 g, 53.2 mmol). The mixture was stirred overnight under N ₂ atmosphere and 120 ℃. After cooling to room temperature, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (PE / EA = 1/1) to give a crude product which was purified by flash column chromatography (H ₂ O / MeOH = 100: 0 to 0: 100) to give the product as a white solid (2.3 g, yield 37.6%). MS (m / z): 231 [M + H] &lt; ^{+ &}

(D) Methyl 6-chloro-3-phenylpyridazine-4-carboxylate

The mixture of methyl 6-hydroxy-3-phenylpyridazine-4-carboxylate (2.3 g, 10 mmol) dissolved in POCl ₃ (10 mL) was stirred at 110 ° C for 6 hours. The excess POCl ₃ was removed in vacuo and an aqueous NaHCO ₃ solution was added. The mixture was concentrated to give a crude product which was further purified by silica gel column chromatography (PE / EA = 3/1) to give the product as a red solid (2 g, yield 80.6%). MS (m / z): 249 [M + H] &lt; ^{+ &}

(E) 6-Chloro-3-phenylpyridazine-4-carboxylic acid

To a solution of methyl 6-chloro-3-phenylpyridazine-4-carboxylate (2 g, 8.06 mmol) in MeOH (10 mL) and H ₂ O (1 mL) was added NaOH (0.64 g, 16.12 mmol) . This mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to a hydrochloric acid solution until pH ~ 3. The mixture was concentrated to give the crude product in the form of a red solid which was used as such in the subsequent step reaction without further purification. MS (m / z): 235 [M + H] &lt; ^{+ &}

(F) 6-Chloro- N -Methoxy- N -Methyl-3-phenylpyridazine-4-carboxamide

To a solution of 6-chloro-3-phenylpyridazine-4-carboxylic acid (1.89 g, 8.06 mmol), N, O-dimethylhydroxyamine hydrochloride (1.56 g, 16.12 mmol), HBTU (6.11 g, a mixture of, 16.12 mmol) and _{Et 3 N (2.44 g, 24.18} mmol) was stirred at room temperature overnight. The reaction mixture was concentrated and the resulting residue was purified by flash column chromatography (PE / EA = 3/1) to give the product as a yellow solid (1.75 g, yield 78.4%). MS (m / z): 278 [M + H] &lt; ^{+ &}

(G) N -Methoxy-6 - ((4-methoxybenzyl) amino) - N -Methyl-3-phenylpyridazine-4-carboxamide

To a solution of (4-methoxyphenyl) methanamine (1.74 g, 12.68 mmol) and 6-chloro- N -methoxy- N -methyl-3-phenylpyridazine- g, 6.32 mmol) was stirred at 130 &lt; 0 &gt; C overnight. After cooling to room temperature, this solution was extracted with EA. The organic phase was concentrated and purified by flash column chromatography (H ₂ O / MeOH = 100: 0 to 0: 100) to give the product as a yellow solid (1.8 g, yield 75%). MS (m / z): 379 [M + H] &lt; ^{+ &}

(H) 6 - ((4-methoxybenzyl) amino) -3-phenylpyridazine-4-carbaldehyde

Dissolved under -20 ℃ and N ₂ atmosphere in anhydrous THF (30 mL), N-methoxy-6 - ((4-methoxybenzyl) amino) - N-methyl-3-phenyl-pyridazine-4-carboxamide ( 1.8 g, 4.76 mmol) in THF (20 mL) was added dropwise DIBAL-H (14.3 g, 14.28 mmol). Then, the mixture was warmed to room temperature and stirred for 4 hours. The mixture was then quenched with aqueous NH ₄ Cl and extracted with EA. The organic phase was concentrated and purified by flash column chromatography (PE: EA = 100: 0 to 1: 1) to give the product as a yellow oil (0.7 g, 46% yield). MS (m / z): 320 [M + H] &lt; ^{+ &}

(I) ( E ) - N ((6 - ((4-methoxybenzyl) amino) -3-phenylpyridazin-4-yl) methylene) -2-methylpropane-

6 N ₂ in an atmosphere dissolved in anhydrous THF (30 mL) - (( 4- methoxybenzyl) amino) -3-phenyl-pyridazin-4-Cavalli formaldehyde (700 mg, 2.2 mmol) and 2-methyl-propane-2 (399 mg, 3.3 mmol) in tetrahydrofuran (5 mL) was added Ti (OEt) ₄ (3 mL). The mixture was stirred at 100 占 폚 overnight. After cooling to room temperature, the mixture was treated with 2 mL H ₂ O and filtered, and the filtrate was extracted with EA. The organic phase was concentrated and the resulting residue was purified by flash column chromatography (H ₂ O: MeOH = 100: 0 to 0: 100) to give the product as a yellow solid (450 mg, 48% yield). MS (m / z): 423 [M + H] &lt; ^{+ &}

(J) N - (1- (6 - ((4-methoxybenzyl) amino) -3-phenylpyridazin-4-yl) ethyl) -2- methylpropane-

In N ₂ atmosphere and 0 ℃ dissolved in anhydrous THF (30 mL) (E) - N - ((6 - ((4- methoxybenzyl) amino) -3-phenyl-pyridazin-4-yl) methylene) -2 -Methylpropane-2-sulfonamide (450 mg, 1.07 mmol) in dichloromethane (5 mL) was added dropwise MeMgBr (1.07 mL, 3.21 mmol). The mixture was then stirred at 0 &lt; 0 &gt; C for a further 2 hours. The reaction was then stopped by the addition of aqueous NH ₄ Cl and the reaction mixture was extracted with EA. The organic phase was washed with saturated brine was concentrated after drying over anhydrous Na ₂ SO _4. The resulting residue was used in the subsequent step reaction without further purification. MS (m / z): 439 [M + H] &lt; ^{+ &}

(K) benzyl (1- (6 - ((4-methoxybenzyl) amino) -3-phenylpyridazin-4-yl) ethyl) carbamate

To a solution of N - (1- (6 - ((4-methoxybenzyl) amino) -3-phenylpyridazin-4yl) ethyl) -2-methylpropane- mg, 1.07 mmol) was added concentrated hydrochloric acid solution (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated to 5- (1-aminoethyl) to remove excess solvent and dried - N - (4- methoxybenzyl) of 6-phenyl-pyridazin-3-amine The crude product obtained as, which was mixed and again DCM (20 mL), benzyl (2,5-dioxolanyl Sophie-1-yl) carbonate (533 mg, 2.14 mmol) and Et ₃ N ₍₃ mL) was dissolved in. The mixture was stirred at room temperature overnight. The reaction mixture was then treated with H ₂ O and extracted with DCM. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product which was used directly in the next step reaction without further purification. MS (m / z): 469 [M + H] &lt; ^{+ &}

(L) 5- (1-Aminoethyl) -6-phenylpyridazin-3-amine

(1- (6 - ((4-methoxybenzyl) amino) -3-phenylpyridazin-4-yl) ethyl) carbonate (501 mg, 1.07 mmol) dissolved in CF ₃ COOH (3 mL) Lt; / RTI &gt; for 12 hours. The solution was then adjusted to an aqueous Na ₂ CO ₃ solution until pH ~ 7, concentrated and the residue was purified by flash column chromatography (H ₂ O: MeOH = 100: 0 to 0: 100) To give the product (214 mg, yield 93%). MS (m / z): 215 [M + H] &lt; ^{+ &}

(M) tert Butyl (1- (6-amino-3-phenylpyridazin-4-yl) ethyl) carbamate

5- (1-aminoethyl) 6-phenyl-pyridazin-3-amine (214 mg, 1 mmol) and Et ₃ N (0.5 mL) was added di-dissolved in EtOH (10 mL) - tert - butyl dicarbonate ( 218 mg, 1 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated to give the crude product, which was used directly for the next step reaction without further purification. MS (m / z): 315 [M + H] &lt; ^{+ &}

(N) tert -Butyl (1- (6-phenylimidazo [1,2- b ] Pyridazin-7-yl) ethyl) carbamate

To a solution of tert -butyl (1- (6-amino-3-phenylpyridazin-4-yl) ethyl) carbamate (314 mg, 1 mmol) in EtOH (10 mL) was added NaHCO ₃ (252 mg, 2-Chloroacetaldehyde (3 mL, 40%) was added. The mixture was stirred at 80 &lt; 0 &gt; C for 2 hours. After cooling to room temperature, aqueous NaHCO ₃ solution was added to the solution until the pH was ~ 8. The mixture was concentrated and the resulting residue was purified by flash column chromatography (H ₂ O: MeOH = 100: 0 to 0: 100) to give the product as a yellow solid (90 mg, yield 27%). MS (m / z): 339 [M + H] &lt; ^{+ &}

(O) 1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethanamine

To a solution of tert -butyl (1- (6-phenylimidazo [1,2- b ] pyridazin-7-yl) ethyl) carbamate (45 mg, 0.13 mmol) in MeOH (3 mL) (0.2 mL). The mixture was stirred at room temperature for 1 hour and then concentrated to give the crude product, which was used directly in the next step reaction without further purification. MS (m / z): 239 [M + H] &lt; ^{+ &}

(P) 4-Amino-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

was dissolved in n -BuOH (5 mL) 1- ( 6- phenyl imidazole crude [1,2- b] pyridazin-7-yl) ethanamine (31 mg, 0.13 mmol) and 4-amino-6-chloropyrimidin 5-carbonitrile (20 mg, 0.13 mmol) and DIPEA (50 mg, 0.39 mmol) was stirred at 130 &lt; 0 &gt; C overnight. After cooling to room temperature the solution was concentrated and the resulting residue was purified by flash column chromatography (H ₂ O: MeOH = 100: 0 to 0: 100) to give the product as a white solid (45 mg, yield 100 %). MS (m / z): 357 [M + H] &lt; ^{+ &}

^{1 H NMR (400 MHz, CD} 3 OD) δ: 8.055 (s, 1H), 8.012 (s, 1H), 7.881 (s, 1H), 7.711 (d, J = 1.2 Hz, 1H), 7.642-7.618 ( m, 2H), 7.494-7.441 (m, 3H), 5.440-5.389 (m, 1H), 1.401 (d, J = 6.8 Hz, 3H).

The compound (2)

4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

Was dissolved in CHCl ₃ (10 mL) 4- amino-6 - ((1- (6-phenyl-imidazole crude [1,2- b] pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile (35 mg, 0.1 mmol) and NCS (26 mg, 0.2 mmol) was stirred at 80 &lt; 0 &gt; C for 6 hours. The mixture was cooled to room temperature and concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (DCM / MeOH) to give 15 mg of the desired product. MS (m / z) = 391 [M + H] &lt; ⁺ &gt;.

¹ H NMR (400 MHz, CD ₃ OD)?: 8.032 (s, IH), 7.882 (s, IH), 7.715 (s, IH), 7.667-7.643 (m, 2H), 7.491-7.474 ), 5.445-5.391 (m, 1H), 1.408 (d, J = 7.2 Hz, 3H).

Compounds (3) and (4)

( R ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile and ( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

The racemic compound (2) was passed through chiral HPLC to provide optically pure enantiomeric compounds (3) and (4) (HPLC conditions: column: Dyecell IA 4.6 x 250 mm; mobile phase: EtOH / DEA = 0.10; flow rate = 1.0 mL / min; detector: UV 254 nm). The primary eluate (Compound (4), S-isomer, Rt = 6.833 min) was 100% ee, MS (m / z): 391 [M + H] ⁺ . 98.07% ee and MS (m / z): 391 [M + H] &lt; ⁺ &gt; were the second eluting compounds (compound (3), R isomer, Rt = 12.51 min).

Compound (3): 1H NMR (400 MHz, CD 3 OD) δ: 8.03 (s, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 7.68 - 7.61 (m, 2H), 7.51 - 7.44 (m, 3H), 5.44-5.39 (m, 1H), 1.40 (d, J = 6.9 Hz, 3H).

Compound (4): 1H NMR (400 MHz, CD 3 OD) δ: 8.04 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.72 (s, 1H), 7.69 - 7.64 (m, 2H), 7.53-7.44 (m, 3H), 5.48-5.37 (m, 1H), 1.40 (d, J = 6.9 Hz, 3H).

Compound (4)

( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

(A) 3,6-dichloro- N -Methoxy- N - methylpyridazine-4-carboxamide

(80.0 g, 0.41 mol), N, O -dimethylhydroxylamine hydrochloride (58.0 g, 0.59 mol) and HBTU (302.0 g, 0.80 mol) dissolved in DCM (1.0 L) mol) in Et ₃ N (160.0 g solution, was added at 1.58 mol) to 0 ℃. The reaction mixture was stirred at 0 &lt; 0 &gt; C for another hour and then at room temperature for 7 hours. The mixture was washed with water (200 mL x 3). The organic phase was concentrated in vacuo and the resulting residue was purified by flash column chromatography (PE: EA = 5: 1 to 1: 2) to give 60 g of 3,6-dichloro- N -methoxy- N- methylpyridazine- 4-carboxamide. MS (m / z) = 236 [M + H] &lt; ⁺ &gt;.

(B) 3-Chloro- N -Methoxy-6 - ((4-methoxybenzyl) amino) - N - methylpyridazine-4-carboxamide

A mixture of N -methoxy- N -methylpyridazine-4-carboxamide (20.0 g, 0.08 mol) and (4-methoxyphenyl) methanamine (34.5 g, 0.25 mol) dissolved in DMA (200 mL) And the mixture was stirred at 50 DEG C for 16 hours. The mixture was poured into water (200 mL) and extracted with EA (200 mL). The organic phase was washed with saturated NaCl solution (200 mL x 3). The organic layer was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (PE: EA = 5: 1 to 1: 5) to obtain 30 g of a crude product. MS (m / z) = 337 [M + H] <^+> , 339 [M + 2 + H] <^+> .

^{1 H NMR (400 MHz, CDCl} 3) δ: 7.30 - 7.16 (m, 2H), 6.89 - 6.76 (m, 2H), 6.59 (s, 1H), 5.46 (s, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.76 (s, 3H), 3.43 (s, 3H), 3.30 (s, 3H).

(C) N -Methoxy-6 - ((4-methoxybenzyl) amino) - N -Methyl-3-phenylpyridazine-4-carboxamide

To a solution of 3-chloro- N -methoxy-6- (4-methoxybenzyl) amino- N -methylpyridazine-4-carboxamide (30.0 g, a, 0.09 mol) and phenyl boric acid (16.0 g, 0.13 mol) Pd (PPh to a solution of _{3) 4 (5.1 g, 4.45} mmol) and KOAc (26.0 g, 0.26 mol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 110 &lt; 0 &gt; C overnight and then cooled to room temperature. The mixture was poured into water (300 mL) and extracted with EA (500 mL x 3). The organic layer was concentrated in vacuo and the resulting residue was purified by flash column chromatography to give 40 g of the desired product. MS (m / z) = 379 [M + H] &lt; ⁺ &gt;.

(D) 6-Amino- N -Methoxy- N -Methyl-3-phenylpyridazine-4-carboxamide

A mixture of N -methoxy-6 - ((4-methoxybenzyl) amino) -N -methyl-3-phenylpyridazine-4-carboxamide (40.0 g, 0.10 mol) . The mixture was cooled to room temperature and concentrated in vacuo and the residue obtained was dissolved in DCM (200 mL) and washed with saturated aqueous NaHCO ₃ solution. The aqueous phase was extracted with (DCM + 30% MeOH). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to yield 30 g of crude product. MS (m / z) = 259 [M + H] &lt; ⁺ &gt;.

(E) 6- (2,5-dimethyl-1 H -Pyrrol-l-yl) - N -Methoxy- N -Methyl-3-phenylpyridazine-4-carboxamide

N -methoxy- N -methyl-3-phenylpyridazine-4 carboxamide (30.0 g, 0.11 mol) and hexane-2,5-dione (66.0 g, 0.58 mmol) dissolved in toluene mol) was added TsOH (2.0 g, 0.01 mol). The mixture was stirred overnight in a 120 DEG C dean-stark trap and cooled to room temperature. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (PE: EA = 5: 1 to 2: 1) to give 14 g of product. MS (m / z) = 337 [M + H] &lt; ⁺ &gt;.

(F) 1- (6- (2,5-Dimethyl-1 H -Pyrrol-1-yl) -3-phenylpyridazin-4-yl) ethanone

Dissolved in anhydrous THF (150 mL) 6- (2,5- dimethyl -1 H - pyrrole-1-yl) - N - methoxy - N - methyl-3-phenyl-pyridazine-4-carboxamide (14.0 g , 0.04 mol) was added MeMgBr (27.7 mL, 0.082 mol) under a nitrogen atmosphere at a temperature of -5 ° C to 0 ° C. The mixture was stirred at 0 to 10 [deg.] C for another 2 hours. The mixture was added to saturated NH ₄ Cl solution and the resulting aqueous layer was extracted with EA (100 mL x 3). The organic layer was concentrated in vacuo to give 15 g of crude product. MS (m / z) = 292 [M + H] &lt; ⁺ &gt;.

(G) ( R, E ) - N - (1- (6- (2,5-dimethyl-1 H -Pyrrol-1-yl) -3-phenylpyridazin-4-yl) ethylidene) -2-methylpropane-

Dissolved in anhydrous THF (150 mL) 1- (6- (2,5- dimethyl -1 H - pyrrole-1-yl) -3-phenyl-pyridazin-4-yl) ethanone (15.0 g, 0.05 mol) and (OEt) ₄ (23.0 g, 0.10 mol) was added to a solution of ( R ) -2-methylpropane-2-sulfinamide (9.3 g, 0.08 mol) in a nitrogen atmosphere. The mixture was stirred overnight at 80 ° C and then cooled to room temperature. The mixture was poured into water (100 mL) and the precipitate was filtered off and the filtrate was extracted with EA. The organic layer was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (PE: EA = 5: 1 to 1: 1) to give 12 g of product. MS (m / z) = 395 [M + H] &lt; ⁺ &gt;.

(H) ( R ) - N - (( S ) -1- (6- (2,5-dimethyl-1 H Yl) -3-phenylpyridazin-4-yl) ethyl) -2-methylpropane-2-sulfinamide

Dissolved in anhydrous THF (150 mL) (R, E) - N - (1- (6- (2,5- dimethyl -1 H - pyrrole-1-yl) -3-phenyl-pyridazin-4-yl) ethyl LiB (C ₄ H ₇ ) ₃ (6.08 mL, 0.06 mol) was added to a solution of 2-methyl-2-methylpropane- The mixture was stirred at -78 [deg.] C for additional 2 hours. The mixture was poured into saturated NH ₄ Cl solution and the aqueous phase was extracted with EA (100 mL x 3) while the organic phase was concentrated in vacuo and the residue obtained was purified by silica gel column chromatography (PE: EA = 5: 1 to 1: 1) to give 10 g of the title product. MS (m / z) = 397 [M + H] &lt; ⁺ &gt;.

(I) ( R ) - N - (( S ) -1- (6-amino-3-phenylpyridazin-4-yl) ethyl) -2-methylpropane-

Was dissolved in EtOH (40 mL) and water (40 mL) (R) - N - ((S) -1- (6- (2,5- dimethyl -1 H - pyrrole-1-yl) -3-phenyl-pyrido chopped 4-yl) ethyl) -2-methylpropane-2-sulfinic amide (8.0 g, 0.02 mol) was added NH ₂ ^OH. Of HCl (13.8 g, 0.20 mol) and _{NaHCO 3 (13.5 g, 0.16 mol} ) was added. The mixture was stirred at 90 占 폚 overnight and then cooled to room temperature. This mixture is NH ₃ until pH = 8 ~ 9 ^. H ₂ O aqueous solution. Purification of the residue was concentrated in vacuo and the mixture obtained therefrom by flash column chromatography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) to give the title product of 4.2 g. MS (m / z) = 319 [M + H] &lt; ⁺ &gt;.

(J) ( R ) -2-methyl- N - (( S ) -1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) propane-2-sulfinamide

Was dissolved in EtOH (50 mL) (R) - N - ((S) -1- (6- amino-3-phenyl-pyridazin-4-yl) ethyl) -2-methylpropane-2-sulfinic amide (4.2 g , 0.013 mol) to the solution was added 2-chloro-acetaldehyde (5.15 g, 0.065 mol) and _{NaHCO 3 (2.1 g, 0.026 mol} ). The mixture was stirred at reflux overnight. The mixture was poured into water (50 mL) and the resulting aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were concentrated in vacuo to give 6.5 g of crude product. MS (m / z) = 343 [M + H] &lt; ⁺ &gt;.

 (K) ( S ) -1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethanamine

To a solution of ( R ) -2-methyl- N - (( S ) -1- (6-phenylimidazo [1,2- b ] pyridazin- -Sulphinamide (6.5 g, 0.019 mol) in HCl at room temperature was added HCl solution dissolved in EA (20 mL, 2.44 mmol) at 0 ° C. And concentrated after stirring for 1 hour the mixture at room temperature in vacuo and purifying the residue obtained therefrom by flash column chromatography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) to obtain a crude product of 4.2 g . MS (m / z) = 239 [M + H] &lt; ⁺ &gt;.

(L) ( S ) -4-amino-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

( S ) -1- (6-Phenylimidazo [l, 2- b ] pyridazin-7-yl) ethanamine (3.8 g, 0.016 mol) and 4-amino- DIPEA (6.1 g, 0.048 mol) was added to a solution of 6-chloropyrimidine-5-carbonitrile (3.7 g, 0.024 mol). The mixture was refluxed overnight and then cooled to room temperature. The mixture was concentrated in vacuo and purifying the residue obtained therefrom by flash column chromatography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) to give the title product of 2.6 g. MS (m / z) = 357 [M + H] &lt; ⁺ &gt;.

(M) ( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

Was dissolved in CHCl _{3 (40 mL) (S)} -4- amino-6 - ((1- (6-phenyl-imidazole crude [1,2- b] pyridazin-7-yl) ethyl) amino) pyrimidin- A mixture of 5-carbonitrile (4 g, 0.011 mol) and NCS (2.3 g, 0.017 mol) was refluxed with stirring for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo and the resulting residue was purified by flash column chromatography (DCM / MeOH) to give 1.8 g of the desired product. MS (m / z) = 391 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CDCl} 3) δ: 8.06 (s, 1H), 7.95 (s, 1H), 7.74 - 7.63 (m, 3H), 7.56 - 7.47 (m, 3H), 5.46 (d, J = 5.9 Hz, 1H), 5.43-5.37 (m, 1H), 5.36 (s, 2H), 1.38 (d, J = 6.8 Hz, 3H).

The following compounds were prepared according to the preparation of compound (4) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compounds (5) and (6)

( R ) -4-amino-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile and ( S ) -4-amino-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile

(A) 6-Amino-3-chloro- N -Methoxy- N - methylpyridazine-4-carboxamide

3-Chloro-dissolved in TFA (20 mL) - N-methoxy-6 - ((4-methoxybenzyl) amino) - N-methyl-pyridazin-4-carboxamide (Compound (4-B), 7.4 g , 21.97 mmol) was refluxed and stirred for 2 hours. The mixture was concentrated in vacuo and the residue obtained therefrom was added into a saturated NaHCO ₃ solution. The mixture was extracted for 30 minutes and stirred at room temperature EA and purified the organic layer was concentrated in vacuo and obtained from this residue by flash column chromatography to give 3.84 g of 6- amino-3-chloro - N - methoxy - N - methylpyridinium Choline-4-carboxamide. MS (m / z) = 217 [M + H] &lt; ⁺ &gt;, 219 [M + 2 + H] &lt; ⁺ &gt;.

(B) 3-Chloro-6- (2,5-dimethyl-1 H -Pyrrol-l-yl) - N -Methoxy- N - methylpyridazine-4-carboxamide

To a solution of 6-amino-3-chloro- N -methoxy- N -methylpyridazine-4-carboxamide (3.84 g, 17.73 mmol) and hexane-2,5-dione (8.45 g, 65.91 mmol) in THF (20 mL) was added TsOH (2.0 g, 0.01 mol). The mixture was placed in a four-necked flask reactor, stirred overnight at 120 ° C and cooled to room temperature. The mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography to give 4.2 g of the title product. MS (m / z) = 295 [M + H] &lt; ⁺ &gt;, 297 [M + 2 + H] &lt; ⁺ &gt;.

(C) Synthesis of 6- (2,5-dimethyl-1 H -Pyrrol-l-yl) - N -Methoxy- N -Methyl-3-phenylpyridazine-4-carboxamide

Dioxane (80 mL) and dissolved in water (8 mL) 3- chloro-6- (2,5-dimethyl -1 H - pyrrole-1-yl) - N - methoxy - N - methyl-pyridazin-4 for a solution of the carboxamide (4.2 g, 14.25 mmol) and phenylboric acid (2.61 g, 21.37 mmol), it was added Pd (PPh _{3) 4,} under a nitrogen atmosphere and KOAc. The reaction mixture was stirred at 110 &lt; 0 &gt; C overnight and then cooled to room temperature. The mixture was poured into water (300 mL) and extracted with EA (100 mL x 3). The combined organic layers were concentrated in vacuo and the resulting residue was purified by flash column chromatography to give 4.3 g of product. MS (m / z) = 337 [M + H] &lt; ^{+ &}

(D) 6- (2,5-dimethyl-1 H -Pyrrol-l-yl) -3-phenylpyridazine-4-carbaldehyde

Dissolved in anhydrous THF (30 mL) 6- (2,5- dimethyl -1 H - pyrrole-1-yl) - N - methoxy - N - methyl-3-phenyl-pyridazine-4-carboxamide (4.3 g , 12.78 mmol) in THF (20 mL) was added DIBAL-H (19 mL, 19.17 mmol) at -20 <0> C and under a nitrogen atmosphere. The reaction mixture was further stirred at -20 ° C for 1 hour, poured into water (300 mL) and extracted with EA. The organic layer was concentrated in vacuo and the resulting residue was purified by flash column chromatography to give 0.95 g of the title product. MS (m / z) = 310 [M + MeOH + H] &lt; ^{+ &}

(E) ( R, E ) - N - ((6- (2,5-dimethyl-1 H -Pyrrol-1-yl) -3-phenylpyridazin-4-yl) methylene) -2-methylpropane-

Dissolved in anhydrous THF (20 mL) 6- (2,5- dimethyl -1 H - pyrrole-1-yl) -3-phenyl-pyridazin-4-Cavalli formaldehyde (0.95 g, 3.43 mmol) and (R) -2 -Methylpropane-2-sulfinamide (0.62 g, 5.14 mmol) in DMF ( ₅ mL) was added Ti (OEt) ₄ (1.56 g, 6.85 mmol) in a nitrogen atmosphere. The reaction mixture was refluxed overnight and then cooled to room temperature. The mixture was added to water (5 ml) and the precipitate was filtered off and the resulting filtrate was extracted with EA. The organic layer was concentrated in vacuo and the resulting residue was purified by flash column chromatography to give 1.2 g of the title product. MS (m / z) = 381 [M + H] &lt; ^{+ &}

(F) ( R ) - N - (( S ) -1- (6- (2,5-dimethyl-1 H Yl) -3-phenylpyridazin-4-yl) propyl) -2-methylpropane-2-sulfinamide and ( R ) - N - (( R ) -1- (6- (2,5-dimethyl-1 H -Pyrrol-1-yl) -3-phenylpyridazin-4-yl) propyl) -2-methylpropane-

Dissolved in anhydrous THF (20 mL) (R, E) - N - ((6- (2,5- dimethyl -1 H-pyrrol-1-yl) -3-phenyl-pyridazin-4-yl) methylene) - To a solution of 2-methylpropane-2-sulfinamide (1.2 g, 3.15 mmol) was added EtMgBr (1.58 mL, 4.73 mmol) at -78 <0> C and under a nitrogen atmosphere. The reaction mixture was stirred at -78 ° C for 1 hour. The mixture was poured into water (5 mL) and extracted with EA. The organic layer was concentrated in vacuo and the resulting residue was purified by flash silica gel column chromatography (PE: EA = 1: 0 to 0: 1) to give two products (0.47 g of intermediate (1-7) and the second eluate is the intermediate (I-8) in 0.18 g) afforded a, one of which is (R) - N - (( S) -1- (6- (2,5- dimethyl -1 H - pyrrol-1-yl) -3-phenyl-pyridazin-4-yl) propyl) -2-methyl-propane-2-sulfinic amide, and the other is (R) - N - (( R) -1- (6- (2,5-dimethyl-1 H -pyrrol-1-yl) -3-phenylpyridazin-4-yl) propyl) -2-methylpropane-2-sulfinamide. MS (m / z) = 411 [M + H] &lt; ^{+ &}

(G) ( R ) - N - (( R (6-amino-3-phenylpyridazin-4-yl) propyl) -2-methylpropane- R ) - N - (( S ) -1- (6-amino-3-phenylpyridazin-4-yl) propyl) -2-methylpropane-

To a solution of Intermediate (I-8) (0.18 g, 0.04 mmol) obtained in the final step reaction in EtOH (2.5 mL) and water (2.5 mL) was added NH ₂ OH ^. Of HCl (0.46 g, 6.58 mmol) and _{Et 3 N (0.44 g, 4.38} mmol) was added. The reaction mixture was stirred at 90 &lt; 0 &gt; C overnight and then cooled to room temperature. NH _{3 in the} mixture until pH 8 ~ 9 ^. And concentrated by the addition of H ₂ O aqueous solution of the mixture in vacuo and purifying the residue obtained therefrom by flash column chromatography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) 0.08 g intermediate (I-10 of the ). MS (m / z) = 333 [M + H] &lt; ⁺ &gt;. Intermediate (I-9) was prepared using Intermediate (I-7) under a nitrogen atmosphere.

(H) ( R ) -2-methyl- N - (( R ) -1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) propyl) propane-2-sulfinamide and ( R ) -2-methyl- N - (( S ) -1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) propyl) propane-2-sulfinamide

Intermediate (I-10) 2- chloro-acetaldehyde (0.32 mL, 1.92 mmol) and _{NaHCO 3 (40 mg, 0.48 mmol} ) to a solution of (80 mg, 0.24 mmol) was dissolved in EtOH (5 mL) was added. The mixture was refluxed overnight. The mixture was poured into water (10 mL) and the resulting aqueous layer was extracted with EA (20 mL x 3). Purification of the residue was concentrated in vacuo and combined organic layer obtained therefrom by flash column chroma pato Photography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) to obtain an intermediate (I-12) of 67 mg. MS (m / z) = 357 [M + H] &lt; ⁺ &gt;. Intermediate (I-11) was prepared using intermediate (I-9) under the same conditions.

 (I) ( R ) -1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) propan-l-amine and ( S ) -1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) propan-l-amine

To the solution of intermediate (I-12) (67 mg, 0.19 mmol) dissolved in EA (3 mL) was added HCl solution dissolved in EA (5 N, 1 mL) at 0 占 폚. The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. From this, the obtained residue was dissolved in MeOH NH ^_3. H ₂ O aqueous solution. Evaporating off excess solvent, and the remaining residue was purified by flash column chromatography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) to to give an intermediate (I-14) of 30 mg. MS (m / z) = 253 [M + H] &lt; ⁺ &gt;. Intermediate (I-13) was prepared using intermediate (I-11) under the same conditions.

(J) ( R ) -4-amino-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile and ( S ) -4-amino-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile

To a solution of intermediate (I-14) (30 mg, 0.12 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (27 mg, 0.19 mmol) in n-BuOH (3 mL) mg, 0.24 mmol). The mixture was refluxed overnight. Cooled and concentrated in vacuo and the mixture was cooled to room temperature and purified the residue obtained therefrom by flash column chromatography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) and to obtain an intermediate (I-16) of 30 mg. MS (m / z) = 371 [M + H] &lt; ⁺ &gt;. Intermediate (I-15) was prepared using intermediate (I-13) under the same conditions.

(K) ( R ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile and ( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile

A solution of intermediate (I-16) (30 mg, 0.08 mmol) and NCS (16 mg, 0.12 mmol) dissolved in CHCl ₃ (4 mL) was stirred at reflux for 2 hours. The mixture at room temperature for cooling and concentrated in vacuo and the residue was purified obtained therefrom by flash column chromatography _{(MeOH / H 2 O + 0.5} % NH 3. H 2 O) of 24 mg, one of the target compound as the compound (6) . MS (m / z) = 405 [M + H] &lt; ⁺ &gt;. Another compound (5) was prepared using intermediate (I-15) under the same conditions.

Compound (5): 1H NMR (400 MHz, CD 3 OD) δ 8.03 (s, 1H), 7.92 (s, 1H), 7.73 - 7.69 (m, 3H), 7.53 - 7.50 (m, 3H), 5.29 - 5.25 (m, 1H), 1.83-1.71 (m, 2H), 0.80 (t, J = 6.6 Hz, 3H).

Compound (6): 1H NMR (400 MHz, CD 3 OD) δ 8.04 (s, 1H), 7.93 (s, 1H), 7.72 (dd, J = 7.2 Hz, 2.4 Hz, 3H), 7.56 - 7.51 (m , 3H), 5.27 (dd, J = 9.4 Hz, 5.0 Hz, 1H), 1.76 (qdd, J = 12.4 Hz, 8.3 Hz, 6.1 Hz, 2H), 0.81 (t, J = 7.3 Hz, 3H).

The following compounds were prepared according to the preparation of compounds (5) and (6) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA. More specifically, compounds (14) and (26) were prepared according to the process for the preparation of compound (5); Compounds (18), (19), (24) and (25) were prepared according to the process for the preparation of compound (6).

Retention times (Rt) of the compounds were tested by chiral HPLC. R-HPLC conditions were as follows:

Column: Die Cell IA 4.6 x 250 mm;

Mobile phase: EtOH / DEA = 100 / 0.10;

Flow rate = 1.0 mL / min;

Detector: UV 254 nm.

Rt of compound (5) is 10.774 min, Rt of compound (6) is 5.032 min, Rt of compound (14) is 5.245 min, Rt of compound (18) is 7.030 min, Rt of compound (19) The Rt of the compound (24) is 4.991 min, the Rt of the compound (25) is 20.884 min, and the Rt of the compound (26) is 14.505 min.

Compounds (7) and (8)

R Amino-6 - ((l- (3-chloro-6- (pyridin- 2- yl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile and ( S Amino-6 - ((l- (3-chloro-6- (pyridin- 2- yl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

(A) 3-Chloro-6 - ((4-methoxybenzyl) amino) pyridazine-4-carbaldehyde

To a solution of 3-chloro- N -methoxy-6- (4-methoxybenzyl) amino- N -methylpyridazine-4-carboxamide (10 g, 29.75 mmol) dissolved in anhydrous THF Diisobutylaluminum hydride (89 mL, 89.26 mmol) was added dropwise at 0 占 폚 and a nitrogen atmosphere. This mixture was stirred at room temperature for 2 hours. The reaction of the mixture was then quenched with saturated NH ₄ Cl solution, filtered and the filtrate was extracted with EA (50 mL x 3). Pass the combined organic layer over anhydrous Na ₂ SO ₄ dried and concentrated, and flash column chromatography (PE: EA = 4: 6 ) to give the to give the desired product in 2.4 g. MS (m / z) = 310 [M + H] ⁺ , 312 [M + 2 + H] ⁺ .

(B) ( R, E ) - N - ((3-chloro-6 - ((4-methoxybenzyl) amino) pyridazin-4-yl) methylene) -2-methylpropane-

-6-chloro-3-dissolved in anhydrous THF (30 mL) - (( 4- methoxybenzyl) amino) pyridazine-4-Cavalli formaldehyde (2.4 g, 8.66 mmol) and (R) -2- methylpropane-2 Ti (OEt) ₄ (4 g, 17.32 mmol) was added under nitrogen atmosphere to a solution of sulfinamide (1.6 g, 13 mmol). The mixture was refluxed overnight. The mixture was cooled to room temperature, poured into water (20 mL), filtered and the resulting filtrate was extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , concentrated, and purified by flash column chromatography (PE: EA = 4: 6) to give 1.4 g of the title product. MS (m / z) = 381 [M + H] &lt; ⁺ &gt;, 383 [M + 2 + H] &lt; ⁺ &gt;.

(C) ( R ) - N - (1- (3-chloro-6 - ((4-methoxybenzyl) amino) pyridazin-4-yl) ethyl) -2- methylpropane-

To a solution of ( R, E ) - N - ((3-chloro-6 - ((4- methoxybenzyl) amino) pyridazin- Was added MeMgBr (3.1 mL, 9.21 mmol) at -5 &lt; 0 &gt; C to 0 &lt; 0 &gt; C and under a nitrogen atmosphere. The mixture was stirred at 0 to 10 ° C for 2 hours. The mixture was poured into saturated NH ₄ Cl solution and extracted with EA (20 mL x 3). The organic layer was concentrated in vacuo to give 1 g of the title product. MS (m / z) = 397 [M + H] &lt; ⁺ &gt;, 399 [M + 2 + H] &lt; ⁺ &gt;.

(D) 5- (1-aminoethyl) -6-chloropyridazin-3-amine

Was dissolved in TFA (5 mL) (R) - N - (1- (3- chloro-6 - ((4-methoxybenzyl) amino) pyridazin-4-yl) ethyl) -2-methyl-propan-2 Sulfinamide (1 g, 2.52 mmol) was refluxed and stirred for 3 hours. The mixture was then concentrated in vacuo and the residue obtained was separated between saturated NaHCO ₃ solution and EA. The organic layer was separated and the aqueous layer was extracted with EA (10 mL x 4). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give 308 mg of the title product. MS (m / z) = 173 [M + H] &lt; ⁺ &gt;.

(E) tert Butyl (1- (6-amino-3-chloropyridazin-4-yl) ethyl) carbamate

Was dissolved in DCM (5 mL) 5- (1- Amino-ethyl) -6-chloropyridazin-3-amine (308 mg, 1.79 mmol), (Boc) 2 O (586 mg, 2.68 mmol) and Et ₃ N ( 543 mg, 5.37 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. The mixture was concentrated and chromatographed to 20 ℃ flash column residue obtained therefrom in _{(MeOH: H 2 O = 4} : 6) to give the to give the title product in 150 mg. MS (m / z) = 273 [M + H] &lt; ⁺ &gt;, 275 [M + 2 + H] &lt; ⁺ &gt;.

(F) tert Butyl (1- (6-chloroimidazo [1,2- b ] Pyridazin-7-yl) ethyl) carbamate

To a solution of tert -butyl (1- (6-amino-3-chloropyridazin-4-yl) ethyl) carbamate (150 mg, 0.55 mmol) in EtOH (5 mL) 1.38 mmol) and _{NaHCO 3 (185 mg, 2.2 mmol} ) was added. The mixture was then heated overnight, refluxed and stirred. The mixture was cooled, concentrated and purified by flash column chromatography (DCM: MeOH = 4: 96) to give 76 mg of the title product. MS (m / z) = 297 [M + H] &lt; ⁺ &gt;, 299 [M + 2 + H] &lt; ⁺ &gt;.

(G) tert Butyl (1- (6- (pyridin-2-yl) imidazo [l, 2- b ] Pyridazin-7-yl) ethyl) carbamate

To a solution of tert -butyl (1- (6-chloroimidazo [1,2- b ] pyridazin-7yl) ethyl) carbamate (56 mg, 0.19 mmol) and 2- (dibutyl (pentyl) stannyl) pyridine (140 mg, 0.38 mmol), Pd ₂ (dba) for the solution, under a nitrogen atmosphere of _{3 (17 mg, 0.019 mmol)} , X-phos (18 mg, 0.038 mmol) and Na ₂ CO ₃ (61 mg, 0.57 mmol). The reaction mixture was heated for 4 hours and refluxed and stirred. The mixture was then cooled, concentrated and purified by flash column chromatography (MeOH: H ₂ O = 55: 45) to give 20 mg of the title product. MS (m / z) = 340 [M + H] &lt; ⁺ &gt;.

 (H) 1- (6- (Pyridin-2-yl) imidazo [ b ] Pyridazin-7-yl) ethanamine

Tert dissolved in EA / MeOH (20 mL) - butyl (l- (6- (pyridin-2-yl) imidazo [1,2- b] pyridazin-7-yl) ethyl) carbamate (20 mg, 0.059 mmol) was added 4N HCl solution dissolved in EA (0.059 mL, 0.236 mmol) at 0 &lt; 0 &gt; C. The mixture was heated to 40 占 폚 and further stirred for 0.5 hours. The mixture was then concentrated in vacuo and the resulting residue was purified by flash column chromatography (MeOH / H ₂ O + 0.5% NH ₃ H ₂ O) to give 9 mg of the title product. MS (m / z) = 240 [M + H] &lt; ⁺ &gt;.

(I) 4-Amino-6 - ((1- (6- (pyridin- 2- yl) b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

It was dissolved in n -BuOH (3 mL) 1- ( 6- ( pyridin-2-yl) imidazo [1,2- b] pyridazin-7-yl) ethanamine (9 mg, 0.037 mmol) and 4-amino -6-chloropyrimidine-5-carbonitrile (9 mg, 0.056 mmol) in dichloromethane was added DIPEA (24 mg, 0.185 mmol). The mixture was refluxed overnight. The mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 65: 35 + 0.5% NH ₃ H ₂ O) to give 9 mg of the title product. MS (m / z) = 358 [M + H] &lt; ⁺ &gt;.

(J) ( R Amino-6 - ((l- (3-chloro-6- (pyridin- 2- yl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile and ( S Amino-6 - ((l- (3-chloro-6- (pyridin- 2- yl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

4-Amino-dissolved in _{CHCl 3 (2 mL) -6 -} ((1- (6- ( pyridin-2-yl) yl-imidazo [1,2- b] pyridazin-7) ethyl) amino) pyridin- A solution of 5-carbonitrile (9 mg, 0.025 mmol) and NCS (7 mg, 0.05 mmol) was refluxed with stirring for 1 hour. The mixture was cooled to room temperature and vacuum dried and the resulting residue was purified by chiral prep-HPLC (column: Dicell lA: 20 * 250 mm; mobile phase: 100% EtOH + 0.1% DEA; flow rate: 8 mL / min; : UV 254 nm;) to give 1.8 mg of compound (7) (Rt = 25.2 min) and 2 mg of compound (8) (Rt = 29.1 min).

Compound (7): MS (m / z) = 392 [M + H] +, 1 H NMR (400 MHz, CD 3 OD) δ 8.70 (d, J = 4.9 Hz, 1H), 8.16 (s, 1H) , 8.01 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 1.9 Hz, 1H) (m, 1H), 5.76 (q, J = 7.1 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H).

Compound (8): MS (m / z) = 392 [M + H] ⁺ , ¹ H NMR (400 MHz, CD ₃ OD)? 8.70 (ddd, J = 4.9 Hz, 1.7 Hz, 0.9 Hz, 8.16 (d, J = 0.7 Hz , 1H), 8.01 (td, J = 7.7 Hz, 1.8 Hz, 1H), 7.91 (dt, J = 7.8 Hz, 1.1 Hz, 1H), 7.84 (s, 1H), 7.79 (s, 1H), 7.54-7.50 (m, 1H), 5.76 (q, J = 7.0 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H).

The following compounds were prepared according to the methods of compounds (7) and (8) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

The Rt of the compound (28) is 9.443 min, and the Rt of the compound (29) is 11.080 min. These two compounds were separated according to the conditions of the method (J) of the compounds (7) and (8).

Compound (20)

( S ) -9- (l- (3-Chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -9 H -Purin-6-amine

(A) ( S ) -6-chloro- N ⁴ - (1- (6-phenylimidazo [1, 2- b ] Pyridazin-7-yl) ethyl) pyrimidine-4,5-diamine

This title compound was prepared by the method of compound (4-L).

MS (m / z) = 366 [M + H] &lt; ^{+ &}

(B) ( S ) -6-chloro-9- (1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -9 H - Purine

It was dissolved in EtOH (5 mL) (S) -6- chloro - N ⁴ - (1- (6- phenyl imidazole crude [1,2- b] pyridazin-7-yl) ethyl) pyrimidine-4,5 -Diamine (59 mg, 0.16 mmol) and triethoxymethane (0.5 mL) was stirred at reflux for 30 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (MeOH / H ₂ O + 0.5% NH ₃ .H ₂ O) to give 42 mg of the title product. MS (m / z) = 376 [M + H] &lt; ^{+ &}

(C) ( S ) -9- (1- (6-phenylimidazo [1, 2- b ] Pyridazin-7-yl) ethyl) -9 H -Purin-6-amine

NH ₃ .H ₂ was dissolved in O (2 mL) (S) -6- chloro-9- (1 - (6-phenyl-imidazole crude [1,2- b] pyridazin-7-yl) ethyl) -9 H -purine (42 mg, 0.11 mmol) was reacted in an electromagnetic wave reaction oven at 110 캜 for 30 minutes. The mixture was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified by flash column chromatography to yield 26 mg of the title product. MS (m / z) = 357 [M + H] &lt; ^{+ &}

(D) ( S ) -9- (l- (3-Chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -9 H -Purin-6-amine

The title compound was prepared according to the process for the preparation of compound (4). (M). MS (m / z) = 391 [M + H] &lt; ^{+ &}

^{1 H NMR (400 MHz, dmso} ) δ 8.24 (s, 1H), 7.96 (s, 1H), 7.93 (d, J = 5.2 Hz, 2H), 7.45 - 7.35 (m, 5H), 7.12 (s, 2H ), 5.79 (q, J = 6.9 Hz, 1H), 1.81 (d, J = 7.0 Hz, 3H).

Compound (21)

( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (2 H -Tetrazol-5-yl) pyrimidine-4,6-diamine

(A) ( S ) - N ⁴ - (1- (6-phenylimidazo [1, 2- b ] Pyridazin-7-yl) ethyl) -5- (2 H -Tetrazol-5-yl) pyrimidine-4,6-diamine

A mixture of the compound (4L) (150 mg, 0.42 mmol), sodium azide (165 mg, 2.55 mmol) and ammonium chloride (135 mg, 2.55 mmol) dissolved in anhydrous DMF (4 mL) In an oven for 40 minutes. The mixture was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified by flash column chromatography to give 36 mg of the title product. MS (m / z) = 400 [M + H] &lt; ^{+ &}

(B) ( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (2 H -Tetrazol-5-yl) pyrimidine-4,6-diamine

The title compound was prepared according to the method of compound (4-M). MS (m / z) = 434 [M + H] &lt; ^{+ &}

^{1 H NMR (400 MHz, dmso} ) δ 8.13 (d, J = 6.4 Hz, 2H), 7.90 (s, 1H), 7.67 - 7.62 (m, 2H), 7.55 - 7.49 (m, 3H), 5.39 - 5.23 (m, 1 H), 1.50 (d, J = 6.8 Hz, 3 H).

Compound (27)

(S) -7- (1- (6-phenylimidazo [1,2-b] pyridazin-7-yl)

(A) ( S ) -2- (4-chloro-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidin-5-yl) ethanol

was dissolved in n -BuOH (5 mL) (S ) -1- (6- phenyl imidazole crude [1,2- b] pyridazin-7-yl) ethanamine (the compound (4-K), 100 mg , 0.42 DIPEA (109 mg, 0.84 mmol) was added to a solution of 2- (4,6-dichloropyrimidin-5-yl) ethanol (122 mg, 0.63 mmol). The reaction mixture was stirred overnight at 120 ° C and then at room temperature. The reaction mixture was concentrated and the residue obtained therefrom flash column chromatography, vacuum: to give the ^{_{(MeOH. H 2 O + 0.5}} % NH 3 H 2 O) to give a product of 142 mg. MS (m / z) = 395 [M + H] &lt; ⁺ &gt;.

(B) ( S ) -4-chloro-7- (1- (6-phenylimidazo [l, 2- b ] Pyridazin-7-yl l) ethyl) -7 H - pyrrolo [2,3- d ] Pyrimidine

To a solution of ( S ) -2- (4-chloro-6- ((1- (6-phenylimidazo [1,2- b ] pyridazin- (322 mg, 0.76 mmol) at 0 &lt; 0 &gt; C was added to a solution of the title compound (100 mg, 0.25 mmol) The mixture was stirred at room temperature for 1.5 hours, then poured into saturated Na ₂ S ₂ O ₃ (10 mL) solution and extracted with DCM (30 mL). The organic layer was concentrated in vacuo and the residue obtained therefrom flash column chromatography to give ^{_{(MeOH. H 2 O + 0.5}} % NH 3 H 2 O) to give a product of 55 mg. MS (m / z) = 375 [M + H] &lt; ⁺ &gt;.

(C) ( S ) -7- (1- (6-phenylimidazo [1, 2- b ] Pyridazin-7-yl) ethyl) -7 H - pyrrolo [2,3- d ] Pyrimidin-4-amine

It was dissolved in ammonia solution (3 mL) (S) -4- chloro-7- (1- (6-phenyl-imidazole crude [1,2- b] pyridazin-7-yl) ethyl) -7 H - pyrrolo [2,3- d ] pyrimidine (55 mg, 0.15 mmol) was sealed in a reaction tube, irradiated with electromagnetic waves in an electromagnetic wave reactor at 120 ° C for 30 minutes, and cooled to room temperature. The mixture was concentrated in vacuo and the residue obtained therefrom flash column chromatography purification ^{_{(MeOH. H 2 O + 0.5}} % NH 3 H 2 O) and to obtain a product of 35 mg. MS (m / z) = 356 [M + H] &lt; ⁺ &gt;.

(D) ( S ) -7- (1- (6-phenylimidazo [1, 2- b ] Pyridazin-7-yl) ethyl) -7 H - pyrrolo [2,3- d ] Pyrimidin-4-amine

The title compound was prepared according to the method of compound (4-M). (M). MS (m / z) = 390 [M + H] &lt; ^{+ &}

^{1 H NMR (400 MHz, CD3OD} ) δ 8.10 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.79 - 7.78 (m, 1H), 7.27 (s, 5H), 6.98 (s , 1H), 6.11-6.06 (m, 1H), 1.76 (d, J = 6.9 Hz, 4H).

Compound (30)

( S Amino-6 - ((1- (3-chloro-6- (3,5- difluorophenyl) b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

(A) 3,6-dichloro- N -Methoxy- N - methylpyridazine-4-carboxamide

Dichloropyridazine-4-carboxylic acid (100.0 g, 0.52 mol), N, O -dimethylhydroxylamine hydrochloride (60.6 g, 0.62 mol) and EDCI (118.8 g, 0.62 mol) dissolved in DCM (800 mL) mol) was added dropwise Et ₃ N (288 mL, 2.08 mol) at 0 ° C. The reaction mixture was then stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO ₃ (1 L) and saturated brine (1 L). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , dried and concentrated to obtain 99.7 g of a crude product. Yield: 81%. M / z = 236 [M + H] ⁺ , 238 [M + 2H] ⁺

(B) 6- (Bis (4-methoxybenzyl) amino) -3-chloro- N -Methoxy- N - methylpyridazine-4-carboxamide

3,6-dichloro-dissolved in DMA (800 mL) - N - methoxy - N - methyl-pyridazin-4-carboxamide (100 g, 0.42 mol), HOBT (68 g, 0.51 mol) and Et ₃ N ( 149 g, 1.48 mol) was heated to 50 &lt; 0 &gt; C. After 2 h, the starting material was confirmed to be consumed in TLC and LC-MS. Next, N, N -bis (4-methoxybenzyl) amine (163 g, 0.64 mol) was added and the mixture was stirred overnight at 50 占 폚. The mixture was treated with saturated brine (1 L) and extracted with EA (1 L x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , concentrated, and purified by silica gel column chromatography (PE: EA = 3: 1 to 1: 1) to give 75 g of product. Yield: 40%. MS (m / z) = 457 [M + H] &lt; ⁺ &gt;.

(C) 1- (6- (Bis (4-methoxybenzyl) amino) -3-chloropyridazin-4-yl) ethan-

To a stirred solution of 6- (bis (4-methoxybenzyl) amino) -3-chloro- N -methoxy- N -methylpyridazine-4-carboxamide dissolved in anhydrous THF (100 mL) ) in) was added MeMgBr (9.9 mL, 29.6 mmol) slowly at 5 &lt; 0 &gt; C to 10 &lt; 0 &gt; C under nitrogen protection. The mixture was stirred at room temperature for 2 hours. The mixture was then poured into a saturated aqueous NH ₄ Cl (30 mL) solution and the aqueous layer was extracted with EA (100 mL x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 7.7 g The product was obtained, which was prepared for use at a later step without purification. MS (m / z) = 412 [M + H] &lt; ⁺ &gt;.

(D) ( R, E ) - N - (1- (6- (bis (4-methoxybenzyl) amino) -3-chloropyridazin-4- yl) ethylidene) -2-methylpropane-

To a solution of 1- (6- (bis (4-methoxybenzyl) amino) -3-chloropyridazin-4-yl) ethan-1-one (7.7 g, 18.73 mmol) and ( R ) (-) - (+) - 2-methyl-2-propanesulfinamide (2.5 g, 20.6 mmol) was added dropwise under nitrogen to a solution of Ti (OEt) ₄ (6.4 g, 28.1 mmol). The mixture was heated to reflux overnight. After cooling to room temperature, the mixture was poured into water (100 mL) and the precipitate was filtered. The filtrate was extracted with EA (100 mL x 2), and the combined organic layer was dried over anhydrous Na ₂ SO ₄ , Purification by flash column chromatography (PE: EA = 2: 1) gave 7.9 g of the title compound as a pale yellow oil. Yield: 81%. MS (m / z) = 515 [M + H] &lt; ⁺ &gt;.

(E) ( R ) - N - (( S ) - 1- (6- (bis (4-methoxybenzyl) amino) -3-chloropyridazin-4- yl) ethyl) -2- methylpropane-

Under, -78 ℃ and nitrogen for the LiB (C ₄ H ₇₎ was dissolved in anhydrous _{THF (80 mL) 3 (39} mL, 38.42 mmol) solution of (R, E) - N - (1- (6- ( bis ( (7.9 g, 15.37 mmol). The mixture was stirred at -78 &lt; 0 &gt; C for 2 h The mixture was poured into a saturated aqueous NH ₄ Cl solution (200 mL) and the aqueous phase was extracted with EA (100 mL x 2). The organic phase was dried and concentrated in vacuo and the residue was purified by flash column chromatography MS (m / z) = 518 [M + H] &lt; ⁺ &gt;.

(F) ( R ) - N - (( S Yl) ethyl) -2-methylpropane-2-sulfinamide (prepared as in Example 1)

D dissolved in dioxane (6 mL) and water (2 mL) (R) - N - ((S) -1- (6- ( bis (4-methoxybenzyl) amino) -3-chloropyridazin-4- A solution of Pd (PPh ₃ ) (1 g) was added to a solution of 3,5-difluorophenylboric acid (551 mg, 3.49 mmol) ₄ (201 mg, 0.174 mmol) and KOAC (511 mg, 5.22 mmol). The reaction mixture was heated overnight, refluxed and stirred. After cooling to room temperature, the mixture was treated with water and extracted with EA (10 mL x 2). The organic phase was dried and concentrated in vacuo and the resulting residue was purified by flash column chromatography (PE: EA = 7: 3) to give 635 mg of the desired compound. Yield: 61%. MS (m / z) = 595 [M + H] &lt; ⁺ &gt;.

(G) ( R ) - N - (( S ) - 1- (6-amino-3- (3,5-difluorophenyl) pyridazin-4- yl) ethyl) -2- methylpropane-

It was dissolved in AcOH (3.2 mL) (R) - N - ((S) -1- (6- (bis (4-methoxybenzyl) amino) -3- (3,5-difluorophenyl) pyridazine- Yl) ethyl) -2-methylpropane-2-sulfinamide (635 mg, 1.07 mmol) in dichloromethane (10 mL) was added concentrated sulfuric acid (1.6 mL) at 10 ° C. The mixture was stirred at room temperature for 2 hours. The mixture was then slowly treated with aqueous NaOH (2 M, 45 mL) at 0 ° C until pH = 8-9 and extracted with DCM (30 mL x 3), and the organic layer was washed with anhydrous Na ₂ SO ₄ , dried, concentrated and purified by flash column chromatography (MeOH: H ₂ O = 6: 4 (+ 0.5% ammonia)) to yield 165 mg of the title compound. Yield: 44%. MS (m / z) = 355 [M + H] &lt; ⁺ &gt;.

(H) ( R ) - N - (( S ) -1- (6- (3,5-difluorophenyl) imidazo [1, 2- b ] Pyridazin-7-yl) ethyl) -2-methylpropane-2-sulfinamide

Was dissolved in EtOH (3 mL) (R) - N - ((S) -1- (6- Amino-3- (3,5-difluorophenyl) pyridazin-4-yl) ethyl) -2-methyl propane-2-sulfinic amide (165 mg, 0.47 mmol) in 2-chloro-acetaldehyde (55 mg, 0.70 mmol) and NaHCO ₃ solution (79 mg, 0.94 mmol) was added. The mixture was then heated overnight, refluxed and stirred. The mixture was cooled, concentrated and purified by flash column chromatography (MeOH: H ₂ O = 7: 3 (+ 0.5% ammonia)) to give 150 mg of the compound as a solid. Yield: 84%. MS (m / z) = 379 [M + H] &lt; ⁺ &gt;.

 (I) ( S ) -1- (6- (3,5-difluorophenyl) imidazo [1, 2- b ] Pyridazin-7-yl) ethan-1-amine hydrochloride

Was dissolved in EA (3 mL) (R) - N - ((S) -1- (6- (3,5- difluorophenyl) imidazo [1,2- b] pyridazin-7-yl) ethyl ) -2-methylpropane-2-sulfinamide (150 mg, 0.4 mmol) in dichloromethane (5 mL) was added HCl-EA (2 mL) at 0 ° C. The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give 99 mg of crude product as a pale yellow solid which was used in the next step without purification. MS (m / z) = 275 [M + H] &lt; ⁺ &gt;.

(J) ( S ) -4-amino-6 - ((1- (6- (3,5-difluorophenyl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

was dissolved in n -BuOH (3 mL) (S ) -1- ( 6- (3,5-difluorophenyl) imidazo [1,2- b] pyridazin-7-yl) ethane-1-amine hydrochloride DIPEA (186 mg, 1.44 mmol) was added to a solution of 4-amino-6-chloropyrimidine-5-carbonitrile (84 mg, 0.54 mmol) The mixture was refluxed overnight. After cooling to room temperature, the mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 55: 45 (+ 0.5% ammonia)) to yield 95 mg of the title compound as a light yellow solid . Yield: 67%. MS (m / z) = 393 [M + H] &lt; ⁺ &gt;.

(K) ( S ) -4-Amino-6 - ((1- (3-chloro-6- (3,5- difluorophenyl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

CHCl _{3 (3} mL) was dissolved in (S) -4- amino-6 - ((1- (6- (3,5-difluorophenyl) imidazo [1,2- b] pyridazin-7-one ) Ethyl) amino) pyrimidine-5-carbonitrile (95 mg, 0.24 mmol) and NCS (35 mg, 0.27 mmol) were stirred at 70 ° C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 7: 3 (+ 0.5% ammonia)) to give 77 mg of the title compound as a solid . Yield: 75%. MS (m / z) = 427 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.10 (t, J = 1.8 Hz, 1H), 7.96 - 7.86 (m, 1H), 7.82 - 7.72 (m, 1H), 7.40 - 7.26 (m, 2H) , 7.12-6.98 (m, 1H), 5.44 (q, J = 6.8 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H).

The following compounds were prepared according to the method for compound (30) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compound (31)

( S Amino-6 - ((1- (3-chloro-6- (o- tolyl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

(A) ( S ) -5- (1-aminoethyl) -6- (o-tolyl) pyridazin-3-amine

It was dissolved in _{CF 3 COOH (5 mL) (} R) - N - ((S) -1- (6- ( bis (4-methoxybenzyl) amino) -3- (o- tolyl) pyridazin-4-yl ) Ethyl) -2-methylpropane-2-sulfinamide (this compound was prepared by the method of Compound (30-G)) (960 mg, 1.68 mmol) was heated and refluxed with stirring for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo and adjusted to pH = 9 with ammonia, again concentrated and purified by flash column chromatography (MeOH: H ₂ O = 4: 6 (+ 0.5% ammonia) mg of the title compound as a pale yellow solid. Yield: 37%. MS (m / z) = 229 [M + H] &lt; ⁺ &gt;.

(B) tert - butyl ( S ) - (1- (6-amino-3- (o-tolyl) pyridazin-4- yl) ethyl) carbamate

( S ) -5- (1-aminoethyl) -6- (o-tolyl) pyridazin-3-amine (140 mg, 0.61 mmol) and (Boc) ₂ O (200 mg, 0.92 mmol) was stirred at room temperature overnight. The mixture was then concentrated at 20 占 폚 and the resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 4: 6 (+ 0.5% ammonia)) to obtain 140 mg of the title compound as a light yellow solid . Yield: 70%. MS (m / z) = 329 [M + H] &lt; ⁺ &gt;.

(S) - (1- (6- (o-tolyl) imidazo [1,2- b] pyridazin-7-yl) ethyl) carbamate

This compound was prepared according to the method of Compound (30-H). MS (m / z) = 353 [M + H] &lt; ⁺ &gt;.

 (D) ( S ) -1- (6- (o-tolyl) imidazo [l, 2- b ] Pyridazin-7-yl) ethan-l-amine

This compound was prepared according to the method of Compound (30-I). MS (m / z) = 253 [M + H] &lt; ⁺ &gt;.

(E) ( S ) -4-amino-6 - ((1- (6- (o-tolyl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared according to the method of Compound (30-J). MS (m / z) = 371 [M + H] &lt; ⁺ &gt;.

(F) ( S Amino-6 - ((1- (3-chloro-6- (o- tolyl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of compound (4-M). MS (m / z) = 405 [M + H] &lt; ⁺ &gt;.

¹ H NMR (400 MHz, CD ₃ OD)? 8.08 (s, 1H), 7.90-7.66 (m, 2H), 7.53-7.16 (m, 4H), 5.33-5.22 m, 3H), 1.45 (d, J = 31.3 Hz, 3H).

The following compounds were prepared according to the method of compound (31) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compound (33)

( S ) -4 - ((l- (3-Chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) -6- (methylamino) pyrimidine-5-carbonitrile

(A) ( S ) -4-chloro-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

( S ) -1- (6-Phenylimidazo [1,2- b ] pyridazin-7-yl) ethan-1- amine was prepared according to the method of Compound (30-I). The title compound was prepared by the method of Compound (30-J). MS (m / z) = 376 [M + H] &lt; ⁺ &gt;.

(B) ( S ) -4- (methylamino) -6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

( S ) -4-chloro-6 - ((1- (6-phenylimidazo [1,2- b ] pyridazin-7-yl) ethyl) amino) pyrimidine- a mixture of 0.146 mmol) and _{CH 3 NH 2 (CH 3 OH} , 35%) (2 mL) at 120 ℃ for 1.5 hours and the mixture was stirred at the electromagnetic wave reactor. The residue obtained after concentration was purified by flash chromatography (H ₂ O: MeOH = 3: 2-2: 3) to give 15.0 mg of the product as a white solid. Yield 28%. MS (m / z) = 371 [M + H] &lt; ⁺ &gt;.

(C) ( S ) -4 - ((l- (3-Chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) -6- (methylamino) pyrimidine-5-carbonitrile

This compound was prepared according to the method of Compound (40-M). (M). MS (m / z) = 405 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.03 (s, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.69 - 7.65 (m, 2H), 7.51 - 7.45 (m, 3H) , 5.42 (q, J = 6.9 Hz, 1H), 2.90 (s, 3H), 1.38 (d, J = 6.9 Hz, 3H).

The following compounds were prepared according to the method of compound (33) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compound (37)

( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (3-fluorophenyl) pyrimidine-4,6-diamine

(A) ( S ) -5-Bromo-6-chloro- N - (1- (6-phenylimidazo [1, 2- b ] Pyridazin-7-yl) ethyl) pyrimidin-4-amine

This compound was prepared according to the method of Compound (30-J). MS (m / z) = 431 [M + H] &lt; ⁺ &gt;.

(B) ( S ) -5-Bromo- N ⁴ - (1- (6-phenylimidazo [1, 2- b ] Pyridazin-7-yl) ethyl) pyrimidine-4,6-diamine

( S ) -5-bromo-6-chloro- N- (1- (6-phenylimidazo [1,2- b ] pyridazin-7-yl) ethyl) pyrimidin- , 1.97 mmol), ammonium hydroxide solution (5 mL, 36%) and EtOH (2 mL) was irradiated with electromagnetic waves in an electromagnetic wave reactor at 150 ° C for 4 hours. After cooling to room temperature, the mixture was concentrated in vacuo to give 1 g of crude product, which was used in the next step without purification. MS (m / z) = 441 [M + H] &lt; ⁺ &gt;.

(C) ( S ) -5-Bromo- N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) pyrimidine-4,6-diamine

This compound was prepared by the method of compound (4-M). MS (m / z) = 446 [M + H] &lt; ⁺ &gt;.

(D) ( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (3-fluorophenyl) pyrimidine-4,6-diamine

This compound was prepared according to the method of Compound (30-F). MS (m / z) = 460 [M + H] &lt; ⁺ &gt;.

¹ H NMR (400 MHz, CD ₃ OD)? 7.92 (s, 1H), 7.88 (s, 1H), 7.76-7.64 (m, 3H), 7.62-7.45 3H), 5.37 (q, J = 7.0 Hz, 1H), 1.20 (d, J = 6.9 Hz, 3H).

The following compounds were prepared according to the method of compound (37) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compound (42)

( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) (methyl) amino) pyrimidine-5-carbonitrile

(A) ( S ) -4-chloro-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared according to the method of Compound (30-J). MS (m / z) = 376 [M + H] &lt; ⁺ &gt;.

(B) ( S ) -4-chloro-6- (methyl (1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

( S ) -4-chloro-6- ((1- (6-phenylimidazo [l, 2- b ] pyridazin-7yl) ethyl) amino) pyrimidine-5-carbonitrile mmol) were dissolved in anhydrous THF (4 mL). The mixture was cooled to 0 &lt; 0 &gt; C and NaH (60%, suspension in mineral oil, 11.2 mg, 0.28 mmol) was added. After stirring for 0.5 hours at room temperature, the mixture was cooled back to 0 ℃ then here was a _{CH 3 I (39.6 mg, 0.28} mmol) was added dropwise to. The mixture was stirred at room temperature overnight. This mixture was added to H ₂ O (8 mL), stirred for 5 minutes and then extracted with DCM. The combined organic layers were concentrated and the resulting residue was purified by flash column chromatography (DCM: MeOH = 19: 1-9: 1) to give 32.0 mg of the product as a white solid. Yield 45%. MS (m / z) = 386 [M + H] &lt; ⁺ &gt;.

(C) ( S ) -4-amino-6- (methyl (1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of Compound (37-B). MS (m / z) = 371 [M + H] &lt; ⁺ &gt;.

(D) ( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylamidazo [ b ] Pyridazin-7-yl) ethyl) (methyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of compound (4-M). MS (m / z) = 405 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.12 (d, J = 1.0 Hz, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.43 - 7.37 (m, 2H), 7.31 - 7.23 (m, 3H), 6.25 (q, J = 6.7 Hz, 1H), 2.77 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H).

Compound (43)

( R ) -4-amino-6 - ((1- (3-chloro-6- (3- fluorophenyl) imidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile

(A) 3-Chloro-6 - ((4-methoxybenzyl) amino) pyridazine-4-carbaldehyde

This compound was prepared according to the method of (7) and (8-A). MS (m / z) = 310 [M + H] ⁺ , 312 [M + 2 + H] ⁺ .

(B) ( R, E ) - N - ((3-chloro-6 - ((4-methoxybenzyl) amino) pyridazin-4-yl) methylene) -2-methylpropane-

This compound was prepared according to the method of (7) and (8-B). MS (m / z) = 381 [M + H] &lt; ⁺ &gt;, 383 [M + 2 + H] &lt; ⁺ &gt;.

(C) ( R ) - N - (1- (3-chloro-6 - ((4-methoxybenzyl) amino) pyridazin-4-yl) ethyl) -2- methylpropane-

This compound was prepared according to the method of (7) and (8-C). MS (m / z) = 411 [M + H] ⁺ , 413 [M + 2 + H] ⁺ .

(D) ( R ) - N - (( R 4-yl) propyl) -2-methylpropane-2-sulfinamide (prepared according to the method described in Example 1)

This compound was prepared by the method of Compound (4-C). MS (m / z) = 471 [M + H] &lt; ^{+ &}

(E) ( R ) - N - (( R ) -1- (6-amino-3- (3-fluorophenyl) pyridazin-4-yl) propyl) -2- methylpropane-

(R) - N - ((R) -1- (3- (3-fluorophenyl) -6 - ((4-methoxybenzyl) amino) pyridazin-4-yl) propyl) -2-methyl-propane -2-sulfinamide (1.1 g, 2.34 mmol) was dissolved in HOAc (5.5 mL). The mixture was cooled to 10 ℃ and slowly added dropwise to concentrated _{H 2 SO 4 (2.75 mL)} . After stirring for 1 hour at room temperature, the mixture was added dropwise to a solution of 8.0 g of NaOH in ice water (100 mL), stirred for 5 minutes, and then extracted with DCM (100 mL). The combined organic layer was concentrated, The obtained residue was purified by flash column chromatography (H ₂ O: MeOH = 3: 2 - 2: 3 (+ 0.5% NH ₃ .H ₂ O)) to obtain 545.0 mg of the desired product in the form of a light brown solid. 66%. MS (m / z) = 351 [M + H] &lt; ⁺ &gt;.

(F) ( R ) - N - (( R ) -1- (6- (3-fluorophenyl) imidazo [1, 2- b ] Pyridazin-7-yl) propyl) -2-methylpropane-2-sulfinamide

This compound was prepared by the method of compound (4-J). MS (m / z) = 375 [M + H] &lt; ⁺ &gt;.

(G) ( R ) -1- (6- (3-fluorophenyl) imidazo [1, 2- b ] Pyridazin-7-yl) propan-1-amine hydrochloride

This compound was prepared by the method of compound (4-K). MS (m / z) = 271 [M + H] &lt; ⁺ &gt;.

(H) ( R ) -4-amino-6 - ((1- (6- (3-fluorophenyl) imidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of compound (4-L). MS (m / z) = 389 [M + H] &lt; ⁺ &gt;.

(I) ( R ) -4-amino-6 - ((1- (3-chloro-6- (3- fluorophenyl) imidazo [ b ] Pyridazin-7-yl) propyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of compound (4-M). MS (m / z) = 423 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.06 (s, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.73 (d, J = 0.9 Hz, 1H), 7.55 - 7.48 (m, 3H ), 7.28-7.21 (m, 1H), 5.24 (q, J = 5.2 Hz, 1H), 1.89-1.70 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H).

The following compounds were prepared according to the method of compound (43) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compound (51)

( S ) -6-amino-4 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) -5-cyanopyrimidine 1-oxide

MCPBA (53 mg, 0.30 mmol) was added to compound (4) (40 mg, 0.10 mmol) dissolved in DCM (10 mL) at 5 占 폚. The mixture was stirred at room temperature for 5 hours. Concentrated in vacuo and the residue was obtained from it and the mixture flash column chromatography purification ^{_{(MeOH. H 2 O (+}} 0.5% NH 3 H 2 O)) to give the title compound in 15 mg in the form of white solid. Yield: 36%; MS (m / z) = 407 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.20 (s, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.60 - 7.58 (m, 2H), 7.50 - 7.47 (m, 3H) , 5.44-5.39 (m, 1H), 1.47 (d, J = 6.9 Hz, 3H).

Compound (52)

( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carboxylic acid

Compound (4) (50.0 mg, 0.13 mmol) was dissolved in an aqueous solution of NaOH (2.0 mol / L, 2 mL) and EtOH (0.4 mL) was added. The mixture was stirred at 60 占 폚 overnight and then cooled to room temperature. Hydrochloric acid (2 mol / L) was added to adjust the pH value to 8-9. The mixture was concentrated and the resulting residue was purified by flash column chromatography (H ₂ O: MeOH = 3: 2-1: 2) to give 60.0 mg of the product as a white solid. Yield 95%. MS (m / z) = 410 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 10.49 - 10.38 (m, 1H), 7.99 (s, 1H), 7.73 - 7.68 (m, 3H), 7.68 - 7.64 (m, 1H), 7.53 - 7.46 ( m, 3H), 5.33-5.22 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H).

Compound (53)

( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carboxamide

( S ) -4-amino-6 - ((1- (3-chloro-6-phenylimidazo [1,2- b ] pyridazin-7-yl) ethyl) amino) pyrimidine- 20.0 mg, 0.049 mmol), NH ₄ Cl (10.4 mg, 0.19 mmol) and HATU (37.2 mg, 0.098 mmol) were dissolved in DMF (2 mL) followed by the slow addition of DIPEA (12.7 mg, 0.098 mmol). This mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the resulting residue was purified by flash column chromatography (H ₂ O: MeOH = 1: 1-1: 4) to give 14.5 mg of the product as a white solid. Yield 72%. MS (m / z) = 409 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.01 - 7.97 (m, 1H), 7.82 (s, 1H), 7.73 - 7.68 (m, 2H), 7.67 - 7.64 (m, 1H), 7.52 - 7.47 ( m, 3H), 5.33-5.25 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H).

The following compounds were prepared according to the method of compound (53) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compound (55)

( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) -2-hydroxypyrimidine-5-carbonitrile

(A) ( S ) -4-chloro-2- (methylthio) -6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared according to the method of Compound (30-J). MS (m / z) = 422 [M + H] &lt; ^{+ &}

(B) ( S Amino-2- (methylthio) -6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of Compound (37-B). MS (m / z) = 403 [M + H] &lt; ⁺ &gt;.

(C) ( S ) -4-Amino-2- (methylsulfonyl) -6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared according to the method of Compound (51). MS (m / z) = 435 [M + H] &lt; ⁺ &gt;.

(D) ( S Amino-2-hydroxy-6 - ((1- (6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

To a solution of ( S ) -4-amino-2- (methylsulfonyl) -6- (1- (6-phenylimidazo [1,2- b ] pyridazin- Ethyl) amino) pyrimidine-5-carbonitrile (150 mg, 0.34 mmol) and NaOH (2 mL, 2 N) was stirred at room temperature for 1 hour. The mixture was extracted with DCM (20 mL X 3) and the combined organic phases were concentrated to give 200 mg of crude product, which was used in the next step without purification. MS (m / z) = 373 [M + H] &lt; ⁺ &gt;.

(E) ( S ) -4-Amino-6 - ((1- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) -2-hydroxypyrimidine-5-carbonitrile

This compound was prepared by the method of compound (4-M). MS (m / z) = 407 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.00 (s, 1H), 7.78 - 7.67 (m, 3H), 7.55 - 7.40 (m, 3H), 5.44 (q, J = 6.8 Hz, 1H), 1.36 (d, J = 6.9 Hz, 3 H).

Compound (69)

( S Amino-6 - ((1- (3-chloro-6- (2-hydroxyphenyl) imidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

To a solution of ( S ) -4-amino-6 - ((1- (3-chloro-6- (2-methoxyphenyl) imidazo [1,2- b ] pyridazin- ) ethyl) amino) pyrimidine-5-carbonitrile (120 mg, 0.28 mmol, this compound was _{BBr 3 (1.4 mL, 1.4 mmol} ) from, 0 ℃ for solution of how to prepare a) of compound 30, the Added dropwise. The mixture was stirred at room temperature for 6 hours. The mixture was then quenched with MeOH and concentrated, and the resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 7: 3) to give 36 mg of the title compound as a light yellow solid. Yield: 32%. MS (m / z) = 411 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.08 (s, 1H), 7.76 (s, 1H), 7.72 (s, 1H), 7.31 - 7.19 (m, 2H), 6.93 - 6.82 (m, 2H) , 5.39 (d, J = 6.9 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H).

Compound (78)

( S ) -4-Amino-6 - ((1- (3-fluoro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

Was dissolved in CHCl _{3 (15 mL) (S)} -4- amino-6 - ((1- (6-phenyl-imidazole crude [1,2- b] pyridazin-7-yl) ethyl) amino) pyrimidin- N -fluoro- N- (phenylsulfonyl) benzenesulfonamide (886 mg, 2.81 mmol) was added to a solution of 5-carbonitrile (100 mg, 0.28 mmol) The mixture was refluxed with stirring for 32 hours. The mixture was concentrated in vacuo and the resulting residue was purified by thin layer chromatography to give 5 mg of the title compound as a white solid. MS (m / z) = 375 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, CDCl} 3) δ 8.05 (s, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.67 - 7.64 (m, 2H), 7.53 - 7.49 (m, 3H), 7.49 - 1H), 7.43 (m, 1H), 7.37 (d, J = 7.0 Hz, 1H), 5.46-5.31 (m, 3H), 1.37 (d, J = 6.8 Hz, 3H).

Compound (79)

( Chiral Yl) phenyl) imidazo [1, 2- (3-chloro-6- b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

(A) 5- (1-aminoethyl) -6-chloropyridazin-3-amine

This compound was prepared by the method of Compound (30-G). ((R) - N - ( 1- (6- ( bis (4-methoxybenzyl) amino) -3-chloropyridazin-4-yl) ethyl) -2-methoxy-propane-2-sulfinic amide compound (30-E).

(B) tert Butyl (1- (6-amino-3-chloropyridazin-4-yl) ethyl) carbamate

This compound was prepared according to the method of Compound (31-B).

(C)  tert-butyl  (1- (6-Chloroimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) carbamate

This compound was prepared by the method of Compound (31-C).

(D)  tert-butyl  (1- (6- (3- (2-hydroxypropan-2-yl) phenyl) imidazo [ b ] Pyridazin-7-yl) ethyl) carbamate

This compound was prepared according to the method of Compound (30-F). MS (m / z) = 397 [M + H] &lt; ⁺ &gt;.

(E) 2- (3- (7- (1-aminoethyl) imidazo [1,2- b ] Pyridazin-6-yl) phenyl) propan-2-ol

Tert TFE dissolved in (3 mL) - butyl (l- (6- (4- (2-hydroxy-propane-2-yl) phenyl) imidazo [1,2- b] pyridazin-7-yl) ethyl) Carbamate (120 mg, 0.30 mmol) was stirred at 140 &lt; 0 &gt; C for 1 hour in an electromagnetic wave reactor. The mixture was concentrated in vacuo to give 95 mg of crude product which was used in the next step without purification. MS (m / z) = 297 [M + H] &lt; ⁺ &gt;.

(F) 4-Amino-6 - ((1- (6- (3- (2-hydroxypropan- b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of compound (4-L). MS (m / z) = 415 [M + H] &lt; ⁺ &gt;.

(G) 4-Amino-6 - ((1- (3-chloro-6- (3- (2-hydroxypropan- b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

This compound was prepared by the method of compound (4-M).

(H) ( Chiral Yl) phenyl) imidazo [1, 2- (3-chloro-6- b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile

The racemic compound (G) was separated by chiral HPLC to give optically pure enantiomeric compound 79 (HPLC conditions: CHIRALPAK Ia 20 mm ID x 25 cm L; mobile phase: EtOH / DEA = 100 / 0.10; / min; detector: UV 254 nm). The eluate (Rf = 3.958 min) was 97.51% ee. MS (m / z): 449 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (400 MHz, dmso} -6d) δ 8.26 (s, 1H), 7.87 (d, J = 5.3 Hz, 2H), 7.78 - 7.76 (m, 2H), 7.60 - 7.58 (m, 1H), 7.43 3H), 1.43 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H).

Compound (79)

The following compounds were prepared according to the method of compound (79-G) using the corresponding intermediates and reagents under appropriate conditions recognized by POSITA.

Compound (81)

( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidine-

(A) ( S ) - N ' -Acetyl-4-amino-6 - ((l- (3-chloro-6-phenylimidazo [ b ] Pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbohydrazide

Dissolved in DMF (2 mL) (S) -4- amino-6 - ((1- (3-chloro-6-phenyl-imidazole crude [1,2- b] pyridazin-7-yl) ethyl) amino) Et ₃ N (64 mg, 0.63 mmol) was added dropwise to a solution of pyrimidine-5-carboxylic acid (88 mg, 0.21 mmol), acethydrazide (19 mg, 0.25 mmol) and HATU (95 mg, 0.25 mmol) did. The mixture was stirred at room temperature overnight. It was confirmed that the starting material was consumed in TLC and LC-MS. The mixture was then partitioned between water (2 mL) and EA (5 mL). The organic layer was separated and the water layer was extracted with EA (5 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give 70 mg of crude product, which was used in the next step without any purification treatment. MS (m / z) = 466 [M + H] &lt; ⁺ &gt;.

(B) ( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidine-

Was stirred and dissolved in anhydrous THF (3 mL) (S) - N '- acetyl-4-amino-6 - ((1- (3-chloro-6-phenyl-imidazole crude [1,2- b] pyridazin- 7- yl) ethyl) amino) pyrimidine-5-carbonyl hydrazide (70 mg, 0.15 mmol) was added N-methyl-a (triethylammonium sulfonyl) carbamate (89 mg, 0.38 mmol) was added. The mixture was heated and refluxed for 3 hours. Next, the mixture was cooled and concentrated. The resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 6: 4) to obtain 10 mg of the title compound. MS (m / z) = 448 [M + H] &lt; ⁺ &gt;.

¹ H NMR (400 MHz, DMSO)? 8.25 (d, J = 6.4 Hz, 1H), 8.14 (s, 1H), 7.90 ), 7.54-7.50 (m, 3H), 7.22 (s, 2H), 5.24-5. 17 (m, 1H), 2.57 (s, 3H), 1.37 (d, J = 6.9 Hz, 3H).

Compound (82)

( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (3-methyl-1,2,4-oxadiazol-5- yl) pyrimidine-

(A) Methyl 4,6-dimethoxypyrimidine-5-carboxylate

To the solution of ethyl 4,6-dichloropyrimidine-5-carboxylate (5 g, 22.73 mmol) in MeOH (50 mL) was added sodium methoxide (4.3 g, 79.55 mmol) in a batch. The reaction mixture was heated and refluxed overnight. The mixture was then added to water (50 mL) and extracted with EA (50 mL x 2). The organic layer was passed through the composite to the inorganic Na ₂ SO ₄ dried and concentrated to give the crude product of 3.9 g. Yield: 88%. MS (m / z) = 199 [M + H] &lt; ⁺ &gt;.

(B) 4,6-Dimethylpyrimidine-5-carboxylic acid

To a solution of methyl 4,6-dimethoxypyrimidine-5-carboxylate (3.9 g, 19.69 mmol) in MeOH (40 mL) was added NaOH (1.6 g, 39.38 mmol) dissolved in water (5 mL). The reaction mixture was then heated for 2 hours and refluxed and stirred. After cooling to room temperature, hydrochloric acid (4 M, 10 mL) was added to the mixture until pH = 4-5. The precipitate was filtered to give 3.5 g of the title compound. Yield: 95%. MS (m / z) = 185 [M + H] &lt; ⁺ &gt;.

(C) 4,6-Dimethoxypyrimidine-5-carboxamide

To a solution of 4,6-dimethoxypyrimidine-5-carboxylic acid (2.5 g, 13.58 mmol), ammonium chloride (864 mg, 16.3 mmol) and HATU (6.2 g, 16.3 mmol) in DMF (30 mL) ₃ N (4.1 g, 40.74 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The starting material was consumed in TLC and LC-MS. The mixture was then treated with water (30 mL) to quench the reaction and extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , concentrated and the residue was purified by flash column chromatography (DCM: MeOH = 8: 2) to give 1.3 g of the title compound. Yield: 51%. MS (m / z) = 184 [M + H] &lt; ⁺ &gt;.

(D) ( E ) - N - (1- (dimethylamino) ethylidene) -4,6-dimethoxypyrimidine-5-carboxamide

A solution of 4,6-dimethoxypyrimidine-5-carboxamide (1.3 g, 7.1 mmol) and N, N -dimethylacetamide dimethylacetal (4.7 g, 35.5 mmol) dissolved in anhydrous toluene (20 mL) Was heated at reflux overnight and stirred. The mixture was then concentrated and the resulting residue was purified by flash column chromatography (EA: MeOH = 7: 3) to give 715 mg of the title compound. Yield: 40%. MS (m / z) = 253 [M + H] &lt; ⁺ &gt;.

(E) 5- (4,6-Dimethoxypyrimidin-5-yl) -3-methyl-1,2,4-oxadiazole

(E) - N - a (1- (dimethylamino) ethylidene) -4,6-di-methoxypyrid limiter Dean-5-carboxamide (715 mg, 2.83 mmol), NaOH solution (2 M, 2.4 mL, 4.81 mmol) was added to a solution of hydroxylamine hydrochloride (254 mg, 3.68 mmol). Next, dioxane (8 mL) and AcOH (5.6 mL, 99.05 mmol) were added thereto. The mixture was heated overnight, refluxed and stirred. The mixture was then cooled and concentrated, and the resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 6: 4) to give 131 mg of the title compound. Yield: 21%. MS (m / z) = 223 [M + H] &lt; ⁺ &gt;.

(F) 5- (3-Methyl-1,2,4-oxadiazol-5-yl) pyrimidine-4,6-diol

To a solution of 5- (4,6-dimethoxypyrimidin-5-yl) -3-methyl-1,2,4-oxadiazole (131 mg, 0.59 mmol) dissolved in AcOH (0.2 mL) Concentrated hydrochloric acid (0.2 mL) was added dropwise. Then, the mixture was heated to 50 DEG C and stirred for 3 hours. The mixture was cooled, concentrated and the resulting residue was purified by flash column chromatography (MeOH: H ₂ O = 15: 85) to give 71 mg of the title compound. Yield: 62%. MS (m / z) = 195 [M + H] &lt; ⁺ &gt;.

(G) 5- (4,6-Dichloropyrimidin-5-yl) -3-methyl-1,2,4-oxadiazole

A solution of 5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidine-4,6-diol (71 mg, 0.36 mmol) dissolved in POCl ₃ (1 mL) And stirred for 1 hour. This mixture was added very slowly to the cold and ice water in the form of drops. The aqueous layer was extracted with DCM (5 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give 54 mg of the title compound which was used in the next step without any purification treatment. Yield: 64% MS (m / z) = 231 [M + H] &lt; ⁺ &gt;.

(H) 6-Chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-

THF (1 mL) 5- (4,6- dichloro-pyrimidin-5-yl) -3-methyl-1,2,4-oxadiazole (54 mg, 0.23 mmol) was dissolved in the solution for 5 min NH ₃ And stirred at room temperature for 2 hours. The mixture was then concentrated to give 36 mg of the title compound, which was used in the next step without any purification treatment. Yield: 75%. MS (m / z) = 212 [M + H] &lt; ⁺ &gt;.

(I) (S) -5- (3-Methyl-1,2,4-oxadiazol-5-yl) - N ⁴ - (1- (6-phenylimidazo [1,2- b] pyridazin-7-yl) ethyl) pyrimidine-4,6-diamine

This compound was prepared by the method of compound (4-L). MS (m / z) = 414 [M + H] &lt; ^{+ &}

(J) ( S ) - N ⁴ - (1- (3-chloro-6-phenylimidazo [l, 2- b ] Pyridazin-7-yl) ethyl) -5- (3-methyl-1,2,4-oxadiazol-5- yl) pyrimidine-

This compound was prepared by the method of compound (4-M). MS (m / z) = 448 [M + H] &lt; ^{+ &}

¹ H NMR (400 MHz, CD ₃ OD)? 8.00 (s, 1H), 7.94 (s, 1H), 7.72-7.69 (m, 3H), 7.54-7.49 (m, 3H), 5.53-5.43 1H), 2.45 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H).

Example 2: Fluorescence measurement of PI3K enzyme activity

PI3K kinase containing p110a / p85a and p110γ was purchased from Invitrogen, and p110d / p85a and p110b / p85a were purchased from Millipore.

Primary screening data and IC ₅₀ values were determined according to the Transcreener (TM) kinase assay (Bellbrook, Catalog # 3003-10K). This method was carried out according to the method proposed by the manufacturer. This is a broad and uniform high-throughput screening (HTS) technique using far-infrared competitive fluorescence polarization immunoassay based on ADP detection to observe the activity of the enzyme catalyzing the functional transfer reaction. In summary, transcript kinase analysis was designed with a simple two-part endpoint analysis as follows:

1) Preparation of 25 uL kinase reaction: 10 uL of kinase buffer (50 mM HEPES, 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS, 3 mM MgCl ₂ and 1 mM DTT supplemented immediately), 10 uL 30 uM PIP2 and 10 uM ATP, The compounds were dissolved in DMSO to give a final concentration of compound in the reaction mixture of 1 uM, 0.3 uM, 0.1 uM, 0.037 uM, 0.012 uM, 0.0041 uM, 0.0014 uM and 0.0005 uM while the final concentration of DMSO in the reaction mixture was 2% ) Or a 5 uL control (2% DMSO) was prepared and a 25 uL kinase reaction was performed. The reaction mixture was placed in a predetermined well of a 96-well plate. The plate was sealed and incubated at room temperature for 80 minutes.

2) Next, 25 uL ADP detection mixture was added to each well. The plate was sealed again and incubated at room temperature for 60 minutes. Next, the fluorescence polarization was measured with a Tecan Infinite F500 reader.

The data were analyzed and IC ₅₀ values were obtained using add-in software (Xlfit TM) (version 5.3 of Microsoft Excel).

The inhibition rate was calculated as follows: IH% = (amount of ADP at the bottom of the 2% DMSO well - amount of ADP at the bottom of the test compound well) / 2% amount of ADP at the bottom of the DMSO well x 100%.

The IC ₅₀ (uM) value of some compounds or the inhibition (IH%) at 1 uM is as follows:

Example 3: Inhibition of AKT phosphorylation in Ramos cell lines

Cells were cultured in RPMI 1640 medium containing 6x10 ⁴ / mL Ramos cell line (ATCC, CRL-1596; 10% FBS) in 96-well plates (Beckman Dickinson, No. 356692) in the amount of 80 uL / well and 4,800 cells / Seeded. After 3 hours of incubation at 37 ° C and 5% CO ₂ , the test compound (final concentration of test compound: 1 uM, 0.3 uM, 0.1 uM, 0.037 uM, 0.012 uM, 0.0041 uM, 0.0014 uM And 0.0005 uM) or 0.3% DMSO for 30 min followed by stimulation with 10 uL / well of 1 ug / ml anti-IgM (Jackson Immunoresearch, 709-006-073) for 15-20 min.

1) Cells were fixed with 100 uL of 4% prewarmed paraformaldehyde (2% final concentration) and incubated at room temperature for 45 min.

2) The paraformaldehyde solution was removed. 100 uL of ice-cold methanol was added to each well and the plate was held at 4 DEG C for 30 minutes.

3) Cells were washed three times with 160 uL of PBS.

4) A 1: 350 dilution of rabbit anti-p-AKT (Ser ⁴⁷³ ) antibody (Cell Signaling Technology, 4060 L) dissolved in antibody dilution buffer (1% BSA in PBS) was added to each well in an amount of 40 uL. Plates were incubated overnight at 4 &lt; 0 &gt; C.

5) Cells were washed three times with 160 uL of PBS.

6) A solution of goat anti-rabbit IgG Alexa488 antibody (Invitrogen, A11034) diluted 1: 1,000 in antibody dilution buffer (1% BSA in PBS) was added to each well in an amount of 45 uL. The plates were wrapped in foil to block light and incubated at room temperature for 90 minutes.

7) Cells were washed three times with 160 uL of PBS.

8) 50 uL of 1.5 uM propidium iodide (Sigma: P4170) solution was added to each well to measure the cell number (1.5 mM stock solution of propidium iodide was diluted 1: 1,000 in PBS and thus the final concentration was 1.5 uM ).

9) The plate was incubated at room temperature for 30 minutes and then sealed with cover seal.

10) The plate was placed in the Acumen Explorer and the instrument panel was properly set and scanned.

The data was analyzed and IC ₅₀ values were obtained using the Xlfit (registered trademark) (version 5.3) add-in software from Microsoft Excel.

The IC ₅₀ (uM) values for some compounds are as follows:

Example 4: Inhibition of PI3K d signaling in basophils from human whole blood

1. Reagents and Materials

2. Method

1) Heparin-added human whole blood was mixed and pipetted into a 96-well v-bottom plate, 100 uL per well.

2) 10 uL of stimulation buffer (1 mg / mL stock solution, final concentration of recombinant human IL-3: 20 ng / mL) was added to whole blood samples contained in each well and stirred slowly in a swirling manner. This sample was incubated at 37 占 폚 for 20 minutes.

3) A test compound dilution of 10 uL / well (final concentration of test compound in wells: 1 uM, 0.3 uM, 0.1 uM, 0.037 uM, 0.012 uM, 0.0041 uM, 0.0014 uM and 0.0005 uM) or vehicle (0.2% DMSO) Was added to each well of the plate, and the plate was incubated at 37 DEG C for 1.5 hours.

4) 100 uL of goat anti-human IgE (1 mg / mL stock solution, final concentration of IgE: 0.31 ug / mL) test solution was added to each well of the plate. All wells were further vortexed one more time and incubated at 37 DEG C for 20 minutes.

5) Labeling of the stained antibody: The sample was incubated on ice for 5 minutes to stop the degranulation reaction. 6 uL of stained antibody mixture (anti-CD63-FITC and anti-IgE-PE) was added to each well. The wells were incubated in a vortex agitation and ice bath for 20 minutes and covered to prevent exposure to light.

6) Whole blood samples were eluted with 300 uL of RBC eluent (room temperature, preheated to 20-25 ° C). This sample was vortexed and incubated at room temperature for 15 minutes. (5 min, 250 x g, 4 &lt; 0 &gt; C). The supernatant was inhaled and separated in an amount of about 100 uL per well.

7) The blood sample was eluted one more time as in step (6).

8) Cleaning: The sample was washed once with 0.5 mL of rinsing liquid. Plates were centrifuged (5 min, 250 x g, 4 &lt; 0 &gt; C). The supernatant was inhaled and separated in an amount of about 100 uL per well. Samples of each well were washed and centrifuged one more time as described above.

9) 200 uL of fixative (1% para-aldehyde solution in BSA / PBS) was added to each well. The plate was placed in an ice bath with a cover and cultured until analysis.

10) Flow cytometry: Cells were analyzed by flow cytometry using blue-green light (488 nm argon-ion laser, FACSCalibur, CELLQuest software).

3. Data Analysis

The data were analyzed and IC ₅₀ values were obtained using add-in software (Xlfit TM) (version 5.3 of Microsoft Excel).

The IC ₅₀ (uM) values for some compounds are as follows:

Example 5: In vitro cell proliferation assay of SU-DHL-6 cell line

Growth inhibition assays were performed using 10% FBS supplemented media. Cells were seeded in 96-well plates at a concentration of 15000 cells / well. Different concentrations of test compound dilutions (final concentration of test compound: 1 uM, 0.3 uM, 0.1 uM, 0.037 uM, 0.012 uM, 0.0041 uM, 0.0014 uM and 0.0005 uM) were added after 24 hours. After the test compound was cultured for 72 hours, the number of cells was measured with Cell Count Kit-8 (CCK-8) (Dojindo, Cat # CK04). The absorbance was read at a wavelength of 450 nm with a multi-scan MK3 device (Thermo).

The data were analyzed and IC ₅₀ values were obtained using add-in software (Xlfit TM) (version 5.3 of Microsoft Excel).

The IC ₅₀ (uM) values for some compounds are as follows:

Example 6: Effect of compound (4) on anti-IgD antibody-induced B cell activity of whole blood of rats

B cells (B220 +) in rat whole blood as it is activated by the receptor-Ig to activated with anti -IgD antibodies, and is accompanied by a PI ₃ K path, and also known that the sensitivity to the control by the PI ₃ Kδ inhibitor. After oral administration of the inhibitor the rats have been developed to target pharmacodynamic assay to assess the in vitro PI ₃ Kδ inhibitor activity.

Wistar rats (female, 6 to 8 weeks of age) were used in the experiment. The dose dependency, elapsed time study and PKPD relationship of compound (4) were confirmed for normal Wistar rats. Compound 4 (0.01, 0.03, 0.1, 0.3, 1, 3 mg / kg) dissolved or suspended in vehicle (0.5% CMC-Na, pH 2.1) was orally administered to rats once. Control group (6 rats) received only vehicle. Blood samples were collected retro-orbital bleeding from the rats under isoflurane inhalation anesthesia with a heparin feed tube at defined times (1 hour, 8 hours, 16 hours and 24 hours after dosing). Heparin anti-clotting blood was mixed with anti-rat-IgD and then incubated overnight at 37 ° C and 5% CO ₂ . Fluorescence signals for CD86 in B220 (B cell) positive cells were detected with a flow cytometer (BD FACSCalibur, BD Biosciences) and analyzed with CellQuest software. Plasma was collected and the concentration of compound (4) was measured.

1, the compound (4) in vitro, a dose-and time-dependent manner, in the amount of 0.01 to 3 mg / kg range (p <0.01) in whole blood wherein -IgD induced B cell activation in the rat . The ED ₅₀ value at 2 hours post-dose was <0.01 mg / kg, which corresponds to an EC ₅₀ value of 1.487 ng / mL. The plasma concentration of compound (4) was proportional to dose at a dose ranging from 0.01 mg / kg to 3 mg / kg. A single oral dose of 0.1 mg / kg resulted in almost complete inhibition of B cell activity for up to 24 hours (> 90% inhibition).

Example 7: Effect of compound (4) on rat collagen (II) induced arthritis (CIA) model

Rat collagen-induced arthritis is an experimental model of multiple arthritis, which has been widely used in non-clinical trials of numerous anti-arthritic agents that are either nonclinical or clinical studies or currently being used as therapeutic agents for the disease.

The protective efficacy of compound (4) was assessed in a collagen-induced arthritis (CLA) model of rats. On day 0 and 7, 200 mg of bovine collagen II (IFA, Sigma, US) emulsified in Freund's incomplete adjuvant was intradermally injected into Wistar rats and immunized. The size of the hind paw was measured before and after immunization. In order to evaluate the anti-inflammatory action of compound (4), female Wistar rats that developed type II collagen-induced arthritis were given compound (4) (0.03, 0.1 and 1 mg / kg) or vehicle (%) CMC-Na, pH 2.1) was orally administered (PO) once a day (QD) for a total of 7 days (10th to 16th day) after induction of type II collagen. While the normal group did not administer anything. As a positive control, YiSaiPu (10 mg / kg), that is, human tumor necrosis factor receptor p75 Fc fusion protein, was administered by intraperitoneal injection at days 10, 12 and 14. On the 18th day, the study was terminated. The results of the study are shown in Fig.

As shown in Fig. 2, the foot volumes of vehicle-administered rats were peaked at day 16. Compared with the diseased animals treated at the end of the treatment period, the foot volume was significantly reduced (p <0.01) in all active ingredient-administered groups, except for the lowest dose of compound (4) (0.03 mg / kg).

The curve undercut area (AUC) obtained from the average paw paw time profile was used as a parameter to evaluate the effect of compound (4) on paw volume during several days of dosing. In each dose group, the AUC reduction percentage relative to vehicle treated diseased animals was determined over the range of 0.03 to 1 mg / kg dose capacity. The decrease in the ankle diameter AUC when using the compound (4) was in the range of 15.5% to 99.5% relative to the vehicle control. In the same study, treatment with YiSaiPu (10 mg / kg, QOD) resulted in 81.6% reduction of paw paw AUC compared to animals treated with vehicle.

In conclusion, daily oral administration of compound (4) showed a dose-dependent beneficial effect on parameters associated with type II collagen-induced arthritis in rats.

Claims (9)

A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof for treating a disease responsive to the inhibition of phosphatidylinositol-3-kinase,
The disease responsive to the inhibition of the phosphatidylinositol-3-kinase is an inflammatory disease, autoimmune disease or cancer,
Wherein said inflammatory disease or autoimmune disease is selected from rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus, systemic lupus erythema, psoriasis and multiple sclerosis,
Wherein said cancer is a solid tumor or a blood cancer selected from leukemia, multiple myeloma (MM) and lymphoma, or a pharmaceutically acceptable salt thereof:

Wherein Ar is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, -CN, -OH, -SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 haloalkyl, -O (C _1-6 alkyl), - (C _{1- 6 alkyl) OH, -NH 2, -NH (} C 1- 6 alkyl), -N (C _1-6 alkyl (C _1-6 alkyl) and -S (O) ₂ (C _1-6 alkyl);
The aryl is a single cyclic ring or a carbocyclic hydrocarbon radical of a fused ring having from 6 to 14 ring carbon atoms, wherein the ring is aromatic;
Said heteroaryl is a monocyclic aromatic hydrocarbon radical having 5, 6 or 7 ring atoms and further containing one or more heteroatoms independently selected from N, O and S in the ring and the remaining ring atoms are carbon, or
Is a bicyclic aromatic hydrocarbon radical having from 8 to 12 ring atoms and containing at least one heteroatom independently selected from N, O and S in the ring and the remaining ring atoms are carbon, wherein the ring is aromatic;
Said cycloalkyl being a saturated or partially unsaturated cyclic hydrocarbon radical having one or more rings and having from 3 to 12 carbon atoms;
W is heteroaryl and -N (R ₃₎ is selected from a heteroaryl, wherein the heteroaryl is halo, -CN, -OH, -SH, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl carbonyl, C _1-6 haloalkyl, -O (C ₁ - ₆ alkyl), - (C ₁ - _{6 alkyl) OH, -NH 2, -NH (} C 1-6 alkyl), -N (C _1-6 alkyl) (C _{1- 6} alkyl), -COOH, -C (O) NH 2, -C (O) NH (C 1-6 alkyl), -C (O) N ( C 1-6 alkyl) (C _{1-6 alkyl), -SO 2 (C 1 -} 6 alkyl), phenyl and 5-or 6-membered is optionally substituted with one or more functional groups selected from heteroaryl; It said phenyl or 5-or 6-membered heteroaryl are each halo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -O as substituents of W (C ₁ - ₆ alkyl) , - (C _1-6 alkyl) OH, -NH ₂ , -NH (C _1-6 alkyl), and -N (C _1-6 alkyl) (C _1-6 alkyl) ,
Said heteroaryl is a monocyclic aromatic hydrocarbon radical having 5, 6 or 7 ring atoms and further containing one or more heteroatoms independently selected from N, O and S in the ring and the remaining ring atoms are carbon, or
A bicyclic aromatic hydrocarbon radical having from 8 to 12 ring atoms and containing at least one heteroatom independently selected from N, O and S in the ring and the remaining ring atoms are carbon, wherein the ring is aromatic;
R ₁ is independently selected from H, halo, -CN, C _1-6 alkyl, C _1-6 haloalkyl, - (C _1-6 alkyl) OH, - (C _1-6 alkyl) O (C _1-6 alkyl And C _2-6 alkynyl;
R ₂ is H, C _1-6 alkyl, and C ₃ - ₈ is selected from cycloalkyl, the C _1-6 alkyl and C ₃ - ₈ cycloalkyl, halo, -CN, C _{1- 6} alkyl, C _1-6 Lt; / RTI &gt; is optionally substituted with one or more functional groups selected from halo, haloalkyl and -OH;
R ₃ is H or C _1-6 alkyl; and
m is 1 or 2; 4. The method of claim 1, wherein the leukemia is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML);
Wherein said lymphoma is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), vesicular lymphoma, B-cell lymphoma, T-cell lymphoma and extensive B-large cell lymphoma Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. The method according to claim 1,
W is nitrogen-containing heteroaryl or -N (R ₃ ) nitrogen-containing heteroaryl, said nitrogen-containing heteroaryl being optionally substituted with one or more substituents selected from halo, -CN, -OH, -SH, C _1-6 alkyl, C _1-6 haloalkyl, O (C ₁ - ₆ alkyl), - (C ₁ - _{6 alkyl) OH, -NH 2, -NH (} C 1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl), _{-COOH, -C (O) NH 2} , -C (O) NH (C 1-6 alkyl), -C (O) N ( C 1-6 alkyl) (C _1-6 alkyl), -SO ₂ ( C _1-6 alkyl), phenyl and 5- or 6-membered heteroaryl; As the substituent W of the phenyl and 5-or 6-membered heteroaryl, halo, -CN, -OH, C _1-6 alkyl, C _1-6 haloalkyl, -O (C ₁ - ₆ alkyl), - (C (C _1-6 alkyl) OH, -NH ₂ , -NH (C _1-6 alkyl) and -N (C _1-6 alkyl) (C _1-6 alkyl) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. The method of claim 3,
W is a nitrogen containing heteroaryl or -N (R ₃₎ a nitrogen-containing heteroaryl group, as the nitrogen-containing heteroaryl group is fluoro, chloro, bromo, -CN, -OH, -SH, C 1-6 alkyl, C _{1 - 6} haloalkyl, -NH _2, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl), -COOH, -C (O) NH 2, phenyl and 5 - or 6-membered heteroaryl; As the substituent W of the phenyl and 5-or 6-membered heteroaryl are each halo, -OH, C _1-6 alkyl, -O -, characterized in that optionally substituted with one or more functional groups selected from (C _{1 6} alkyl) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
Wherein said nitrogen-containing heteroaryl is selected from pyrimidinyl, pyrrolopyrimidinyl and furunyl, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
W is

It is selected, each of which is fluoro, chloro, bromo, -CN, -OH, -SH, C 1-6 alkyl, C _{1- 6} haloalkyl, -NH _2, -NH (C _1-6 alkyl) from , -N (C _1-6 alkyl) (C _1-6 alkyl), -COOH, -C (O) NH 2, C (O) NH (C 1-6 alkyl), phenyl and 5-or 6-membered Optionally substituted with one or more functional groups selected from heteroaryl; It said phenyl or 5-or 6-membered heteroaryl are each halo, -CN, -OH, -SH, C 1-6 alkyl, C _1-6 haloalkyl, -O as substituents of W (C ₁ - ₆ alkyl) Optionally substituted by one or more functional groups selected from - (C _1-6 alkyl) OH, -NH ₂ , -NH (C _1-6 alkyl) and -N (C _1-6 alkyl) (C _1-6 alkyl) Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. The method according to claim 6,
W is

It is selected from, each of _{chloro, -CN, -NH 2, -NH (} C 1-6 alkyl), -COOH, -C (O) NH 2, phenyl, pyridyl, oxadiazolyl, pyrazolyl, and tetra Optionally substituted by one or more functional groups selected from the group consisting of halo; Said phenyl, pyridyl, oxadiazolyl, pyrazolyl, or tetrazole each day halo, -OH, C _1-6 alkyl, -O -, characterized in that optionally substituted with one or more functional groups selected from (C _{1 6} alkyl) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. The method according to claim 6,
W is

And, which is fluoro, chloro, bromo, -CN, -OH, -SH, C 1-6 alkyl, C _{1-6 haloalkyl, -NH 2, -NH (C 1-} 6 alkyl), -N ( C _{1- 6} is optionally substituted with alkyl) (C _1-6 alkyl), -COOH, -C (O) NH 2, phenyl and a 5- or 6-membered one or more functional groups selected from heteroaryl; As the substituent W of the phenyl and 5-or 6-membered heteroaryl are each halo, -OH, C _1-6 alkyl, -O -, characterized in that optionally substituted with one or more functional groups selected from (C _{1 6} alkyl) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. 9. The method of claim 8,
W is

And, it _{chloro, -CN, -NH 2, NH (} C 1-6 alkyl), -COOH, -C (O) NH 2, or more of phenyl, pyridyl, oxadiazolyl, one selected from the group consisting of pyrazolyl and tetrazolyl Lt; / RTI &gt; In any being substituted with one or more functional groups selected from - (C _{1 6} alkyl) wherein the phenyl, pyridyl, oxadiazolyl, pyrazolyl, or tetrazol-work each halo, -OH, C _1-6 alkyl, and -O Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.

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